ES2242965T3 - DERIVATIVES OF ARIL-ESTER PHOSPHORAMIDATE OF 2 ', 3'-DIDEHYDRONUCLEOSIDS. - Google Patents
DERIVATIVES OF ARIL-ESTER PHOSPHORAMIDATE OF 2 ', 3'-DIDEHYDRONUCLEOSIDS.Info
- Publication number
- ES2242965T3 ES2242965T3 ES96906832T ES96906832T ES2242965T3 ES 2242965 T3 ES2242965 T3 ES 2242965T3 ES 96906832 T ES96906832 T ES 96906832T ES 96906832 T ES96906832 T ES 96906832T ES 2242965 T3 ES2242965 T3 ES 2242965T3
- Authority
- ES
- Spain
- Prior art keywords
- sup
- compound
- cdcl
- alkyl
- wing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- PTMHPRAIXMAOOB-UHFFFAOYSA-L phosphoramidate Chemical compound NP([O-])([O-])=O PTMHPRAIXMAOOB-UHFFFAOYSA-L 0.000 title description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 125000003118 aryl group Chemical group 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000001301 oxygen Substances 0.000 claims abstract description 19
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 17
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 14
- 229940113082 thymine Drugs 0.000 claims abstract description 12
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 92
- 239000002777 nucleoside Substances 0.000 claims description 32
- 102100034343 Integrase Human genes 0.000 claims description 31
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 31
- 239000002207 metabolite Substances 0.000 claims description 25
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 12
- 239000001226 triphosphate Substances 0.000 claims description 12
- 230000009385 viral infection Effects 0.000 claims description 12
- 208000036142 Viral infection Diseases 0.000 claims description 11
- 230000005764 inhibitory process Effects 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000003835 nucleoside group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 101100277337 Arabidopsis thaliana DDM1 gene Proteins 0.000 claims 2
- 101150113676 chr1 gene Proteins 0.000 claims 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 claims 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 claims 1
- -1 R<SUP>5 </SUP>is H Chemical group 0.000 abstract description 54
- 230000000840 anti-viral effect Effects 0.000 abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 13
- 229910052736 halogen Inorganic materials 0.000 abstract description 5
- 150000002367 halogens Chemical class 0.000 abstract description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical class N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 abstract description 3
- 125000005843 halogen group Chemical group 0.000 abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 abstract description 3
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical compound OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 abstract description 2
- 125000001624 naphthyl group Chemical group 0.000 abstract description 2
- 125000003367 polycyclic group Chemical group 0.000 abstract description 2
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 abstract 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical class [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 abstract 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 45
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 39
- 230000000694 effects Effects 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 229910019142 PO4 Inorganic materials 0.000 description 15
- 239000011159 matrix material Substances 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 239000000460 chlorine Substances 0.000 description 13
- 239000010452 phosphate Substances 0.000 description 13
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 12
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 12
- 208000031886 HIV Infections Diseases 0.000 description 11
- 241000725303 Human immunodeficiency virus Species 0.000 description 11
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 11
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 10
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 9
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 5
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 229940127073 nucleoside analogue Drugs 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 229930024421 Adenine Natural products 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000011785 NMRI mouse Methods 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 229960000643 adenine Drugs 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
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- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 150000007860 aryl ester derivatives Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
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- 125000004122 cyclic group Chemical group 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
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- BTOTXLJHDSNXMW-POYBYMJQSA-N 2,3-dideoxyuridine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(=O)NC(=O)C=C1 BTOTXLJHDSNXMW-POYBYMJQSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Abstract
Description
Derivados de aril-éster fosforamidato de 2',3'-didehidronucleósidos.Aryl ester phosphoramidate derivatives of 2 ', 3'-didehydronucleosides.
La presente invención se refiere a una nueva clase de análogos de nucleósidos y a su uso terapéutico en la profilaxis y el tratamiento de la infección viral, por ejemplo por el virus de la inmunodeficiencia humana (VIH), que se cree que es el agente etiológico en el síndrome de inmunodeficiencia adquirida (SIDA).The present invention relates to a new class of nucleoside analogues and their therapeutic use in the prophylaxis and treatment of viral infection, for example by the human immunodeficiency virus (HIV), which is believed to be the etiologic agent in acquired immunodeficiency syndrome (AIDS).
Ha habido mucho interés por el uso de análogos de nucleósidos como inhibidores del VIH. La 2',3'-didesoxi-2',3'-dideshidrotimidina (d4T) y la 3'-azido-3'-desoxitimidina (AZT) son ambos inhibidores conocidos del VIH [Hitchcock y col., Antiviral Chem. Chemother. (1991), 2, 125; Mansuri y col., Antimicrob. Agents Chemother., (1990), 34, 637]. Se piensa convencionalmente que la inhibición del VIH por estos, y otros análogos de nucleósidos, depende de la conversión del análogo de nucleósido in vivo en el correspondiente 5'-trifosfato por las enzimas quinasa (de la célula huésped). No obstante, esta dependencia absoluta de la activación mediada por quinasas (de la célula huésped) puede conducir a una escasa actividad, la aparición de resistencia, y toxicidad clínica.There has been much interest in the use of nucleoside analogs as HIV inhibitors. 2 ', 3'-dideoxy-2', 3'-dideshydrotimidine (d4T) and 3'-azido-3'-deoxythymidine (AZT) are both known HIV inhibitors [Hitchcock et al., Antiviral Chem. Chemother. (1991), 2 , 125; Mansuri et al., Antimicrob. Agents Chemother., (1990), 34 , 637]. It is conventionally thought that HIV inhibition by these, and other nucleoside analogs, depends on the conversion of the nucleoside analog in vivo into the corresponding 5'-triphosphate by the kinase enzymes (of the host cell). However, this absolute dependence on kinase-mediated activation (of the host cell) can lead to poor activity, the emergence of resistance, and clinical toxicity.
Con el fin de reducir la dependencia de las
enzimas quinasa, se ha sugerido el uso de
pro-fármacos de fosfato enmascarados de las formas
nucleotídicas bioactivas de numerosos análogos de nucleósidos
quimioterapéuticos
[McGuigan y col., Nucleic Acids res.,
(1989), 17, 6065; McGuigan y col., Idem., (1989), 17,
7195; Chawla y col., J. Med. Chem., (1984), 27, 1733;
Sergheraert y col., J. Med. Chem. (1993), 36,
826-830]. En particular, McGuigan y col [J.
Med. Chem. 36, 1048-1052 (1993)] han
informado sobre la preparación de derivados éster arílico de
fosforamidato de AZT. La evaluación in vitro de estos
compuestos reveló que los compuestos tenían actividad
anti-VIH. No obstante, en las células ricas en
timidina quinasa "normales" (TK^{+}), la actividad de tales
compuestos era como mínimo de un orden de magnitud menor que el
nucleósido de origen AZT. Sólo las células deficientes en TK
(TK^{-}), en las cuales la actividad de los derivados éster
arílico de fosforamidato se mantenía virtualmente pero se reducía la
actividad del AZT, la actividad de los derivados excedía la de
AZT.In order to reduce the dependence of the kinase enzymes, the use of masked phosphate pro-drugs of bioactive nucleotide forms of numerous chemotherapeutic nucleoside analogs has been suggested.
[McGuigan et al., Nucleic Acids res., (1989), 17 , 6065; McGuigan et al., Idem., (1989), 17 , 7195; Chawla et al., J. Med. Chem., (1984), 27 , 1733; Sergheraert et al., J. Med. Chem. (1993), 36 , 826-830]. In particular, McGuigan et al [J. Med. Chem. 36 , 1048-1052 (1993)] have reported on the preparation of aryl ester derivatives of AZT phosphoramidate. In vitro evaluation of these compounds revealed that the compounds had anti-HIV activity. However, in "normal" thymidine kinase-rich cells (TK +), the activity of such compounds was at least an order of magnitude less than the nucleoside of AZT origin. Only TK-deficient cells (TK -), in which the activity of the aryl ester derivatives of phosphoramidate was virtually maintained but the activity of AZT was reduced, the activity of the derivatives exceeded that of AZT.
McGuigan y col. [Bioorganic & Medical chemistry Letters., 3(6), 1203-1206 (1993)] también han informado sobre la preparación de derivados triésterfosfato de d4T. De nuevo, la evaluación in vitro de estos compuestos reveló que mientras los compuestos tienen una actividad anti-VIH significativa, la actividad es menor que la del nucleósido de origen d4T en células TK^{+}.McGuigan et al. [Bioorganic & Medical chemistry Letters., 3 (6), 1203-1206 (1993)] have also reported on the preparation of trésterfosphate derivatives of d4T. Again, in vitro evaluation of these compounds revealed that while the compounds have significant anti-HIV activity, the activity is less than that of the nucleoside of d4T origin in TK + cells.
Abraham y Wagner (Nucleosides and Nucleotides 13(9), 1891-1903 (1994)) han informado sobre la preparación de diésteres y triésteres fosforamidato de nucleósidos pero no informan sobre ninguna actividad biológica.Abraham and Wagner (Nucleosides and Nucleotides 13 (9) , 1891-1903 (1994)) have reported the preparation of diesters and tri-esters phosphoramidate nucleosides but do not report any biological activity.
Se ha demostrado que el análogo de nucleósido acíclico 9(2-fosfonometoxietil)adenina (PMEA), y análogos del mismo muestran actividad frente a herpes virus y retrovirus incluyendo el VIH (Calio y col., Antiviral Res., (1994), 23(1), 77-89; Balzarini y col., AIDS, (1991), 5(1), 21-28).It has been shown that the acyclic nucleoside analog 9 (2-phosphonomethoxyethyl) adenine (PMEA), and analogues thereof show activity against herpes viruses and retroviruses including HIV (Calio et al., Antiviral Res., (1994), 23 (1) , 77-89; Balzarini et al., AIDS, (1991), 5 (1) , 21-28).
McGuigan y col. [FEBS Letters 351 (1994) 11-14] han informado sobre ciertos derivados triéster fosfato del análogo de nucleósido inactivo, didesoxiuridina, son inhibidores de la replicación del VIH a niveles \muM.McGuigan et al. [FEBS Letters 351 (1994) 11-14] have reported certain tri-ester phosphate derivatives of the inactive nucleoside analogue, dideoxyuridine, are inhibitors of HIV replication at µM levels.
Hasta la fecha, el enfoque para proporcionar pro-fármacos fosfato enmascarados ha fallado al intensificar las actividades anti-virales de los análogos de los nucleósidos de origen tales como AZT y d4T en células TK^{+}. Además, la aparición de resistencia a los análogos de nucleósidos en su forma 5'-trifosfato bioactiva ha vuelto los profármacos de fosfato enmascarados referidos y sus análogos nucleosídicos de origen potencialmente ineficaces.To date, the approach to provide masked phosphate pro-drugs have failed to intensify the anti-viral activities of nucleoside analogs of origin such as AZT and d4T in TK + cells. In addition, the emergence of resistance to nucleoside analogs in its 5'-triphosphate form bioactive has returned the phosphate prodrugs masked referrals and their nucleoside analogs of potentially origin ineffective
Se ha encontrado ahora que una clase concreta de análogos de nucleósidos enmascarados son inhibidores virales muy potentes tanto en células TK^{-} como TK^{+}, y aún conservan actividad frente a virus resistentes a nucleósidos (v.g. d4T).It has now been found that a specific class of masked nucleoside analogs are very viral inhibitors potent in both TK - and TK + cells, and still retain activity against nucleoside resistant viruses (e.g. d4T).
Según la presente invención se proporciona un compuesto de fórmula (1):According to the present invention a compound of formula (1):
donde:where:
- Ar es un grupo arilo;Ar is a group aryl;
- Y es oxígeno o azufre;And it is oxygen or sulfur;
- X^{1} se selecciona entre O, NR^{3}, S, CR^{3}R^{4}, CR^{3}W^{1} y CW^{1}W^{2} donde R^{3} y R^{4} se seleccionanX1 se selects between O, NR 3, S, CR 3 R 4, CR 3 W 1 and CW 1 W 2 where R 3 and R 4 are selected
- independientemente entre hidrógeno, grupos alquilo y arilo; y W^{1} y W^{2} son heteroátomos;independently between hydrogen, groups alkyl and aryl; and W1 and W2 are heteroatoms;
- X^{6} es CH_{2} y X^{2} se selecciona (independientemente de X^{1}) entre O, NR^{3}, S, CR^{3}R^{4}, CR^{3}W^{1} y CW^{1}W^{2}X 6 is CH2 and X2 is selected (independently of X1) between O, NR 3, S, CR 3 R 4, CR 3 W 1 and CW 1 W 2
- donde R^{3} y R^{4} se seleccionan independientemente entre hidrógeno, grupos alquilo y arilo; y W^{1} y W^{2} son heteroátomos;where R3 and R 4 are independently selected from hydrogen, groups alkyl and aryl; and W1 and W2 are heteroatoms;
- X^{3} es -CR^{1}R^{2}- donde R^{1} y R^{2} se seleccionan independientemente entre hidrógeno, grupos alquilo y arilo; X^{4} es oxígeno;X3 is -CR 1 R 2 - where R 1 and R 2 are selected independently between hydrogen, alkyl and aryl groups; X 4 it is oxygen;
- X^{5} está ausente;X5 is absent;
- Z se selecciona entre O y NR^{5}, donde R^{5} se selecciona entre hidrógeno, grupos alquilo y arilo;Z is selected between O and NR 5, where R 5 is selected from hydrogen, alkyl and aryl groups;
- J se selecciona entre los grupos alquilo;J is selected between the alkyl groups;
- Q se selecciona entre O, NR^{6}, S, CR^{6}R^{7}, CR^{6}W^{3} y CW^{3}W^{4}, donde R^{6} y R^{7} se seleccionanQ is selected between O, NR 6, S, CR 6 R 7, CR 6 W 3 and CW 3 W 4, where R 6 and R 7 are selected
- independientemente entre hidrógeno, grupos alquilo y arilo; y W^{3} y W^{4} son heteroátomos;independently between hydrogen, groups alkyl and aryl; and W3 and W4 are heteroatoms;
- T^{1} y T^{2} están unidos entre sí y juntos se seleccionan entre los gruposT1 and T2 are linked together and together are selected from among groups
-
22
- B es una base de purina o pirimidinaB is a base of purine or pyrimidine
o un derivado o metabolito farmacéuticamente aceptable del mismo.or a derivative or metabolite pharmaceutically acceptable from same.
Los compuestos de la presente invención son potentes agentes anti-virales. En particular, son muy eficaces contra el VIH tanto en células TK^{-} como TK^{+}. Es particularmente sorprendente la actividad de los compuestos de la presente invención frente al VIH resistente a los nucleósidos. Estas observaciones indican que la actividad de estos compuestos no es totalmente dependiente del modo de acción convencional (requiriendo hidrólisis de los enlaces del éster arílico de fosfato y P-X^{1} seguido de la conversión dependiente de quinasa en el derivado 5'-trifosfato), sino que surge de un modo de acción completamente diferente. Los datos experimentales presentados aquí indican que los compuestos y metabolitos de la presente invención actúan directamente como inhibidores de la transcriptasa inversa (RT) por medio de una ruta metabólica y un mecanismo de acción no reconocidos previamente.The compounds of the present invention are potent anti-viral agents. In particular, they are very effective against HIV in both TK - and TK + cells. Particularly surprising is the activity of the compounds of the present invention against nucleoside resistant HIV. These observations indicate that the activity of these compounds does not It is totally dependent on the conventional mode of action (requiring hydrolysis of the aryl phosphate ester bonds and P-X1 followed by conversion dependent on kinase in the 5'-triphosphate derivative), but It arises from a completely different mode of action. The data Experimental presented here indicate that the compounds and metabolites of the present invention act directly as reverse transcriptase (RT) inhibitors via a route metabolic and a mechanism of action not previously recognized.
La referencia en la presente memoria a un grupo alquilo representa un radical hidrocarbilo lineal o ramificado, cíclico o acíclico, saturado o insaturado (v.g. alquenilo o alquinilo). Cuando es cíclico, el grupo alquilo es preferiblemente C_{3} a C_{12}, más preferiblemente C_{5} a C_{10}, más preferiblemente C_{5} a C_{7}. Cuando es acíclico, elgrupo alquilo es preferiblemente C_{1} a C_{16},más preferiblemente C_{1} a C_{6}, más preferiblemente metilo. La referencia en la presente memoria a grupos alcoxi y ariloxi representa grupos alquil-O- y aril-O, respectivamente. La referencia a grupos alcoilo y ariloilo representa alquil-CO- y -aril-CO-, respectivamente.The reference herein to a group alkyl represents a linear or branched hydrocarbyl radical, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl). When it is cyclic, the alkyl group is preferably C 3 to C 12, more preferably C 5 to C 10, more preferably C 5 to C 7. When it is acyclic, the group alkyl is preferably C 1 to C 16, more preferably C 1 to C 6, more preferably methyl. The reference in the present memory to alkoxy and aryloxy groups represents groups alkyl-O- and aryl-O, respectively. Reference to alkoxy and aryloyl groups represents alkyl-CO- and -aryl-CO-, respectively.
La referencia en la presente memoria a un grupo arilo representa un grupo aromático, tal como fenilo o naftilo, o un grupo heteroaromático que contiene uno o más, preferiblemente un, heteroátomo, tal como piridilo, pirrolilo, furanilo y tiofenilo. Preferiblemente, el grupo arilo comprende fenilo o fenilo sustituido.The reference herein to a group aryl represents an aromatic group, such as phenyl or naphthyl, or a heteroaromatic group containing one or more, preferably a, heteroatom, such as pyridyl, pyrrolyl, furanyl and thiophenyl. Preferably, the aryl group comprises phenyl or phenyl replaced.
Los grupos alquilo y arilo pueden ser sustituidos o no sustituidos, preferiblemente no sustituidos. Cuando están sustituidos, estarán presentes preferiblemente de 1 a 3 sustituyentes, preferiblemente 1 sustituyente. Entre los sustituyentes se pueden incluir átomos de halógeno y grupos halometilo tales como CF_{3} y CCl_{3}; grupos que contienen oxígeno tales como oxo, hidroxi, carboxi, carboxialquilo, alcoxi, alcoilo, alcoiloxi, ariloxi, ariloilo y ariloiloxi; grupos que contienen nitrógeno tales como amino, alquilamino, dialquilamino, ciano, azida y nitro; grupos que contienen azufre tales como tiol, alquiltiol, sulfonilo y sulfóxido; grupos heterocíclicos que pueden estar a su vez sustituidos; grupos alquilo, que pueden estar a su vez sustituidos; y grupos arilo, que pueden estar a su vez sustituidos, tales como fenilo y fenilo sustituido. En alquilo se incluyen bencilo sustituido y no sustituido.The alkyl and aryl groups can be substituted or unsubstituted, preferably unsubstituted. When they are substituted, preferably 1 to 3 will be present substituents, preferably 1 substituent. Between the substituents can include halogen atoms and groups halomethyl such as CF 3 and CCl 3; groups that contain oxygen such as oxo, hydroxy, carboxy, carboxy alkyl, alkoxy, alkoxy, alkoxy, aryloxy, aryloyl and aryloxy; groups that contain nitrogen such as amino, alkylamino, dialkylamino, cyano, azide and nitro; sulfur-containing groups such as thiol, alkylthiol, sulfonyl and sulfoxide; heterocyclic groups that can be substituted in turn; alkyl groups, which may be at your once replaced; and aryl groups, which may be in turn substituted, such as phenyl and substituted phenyl. In rent it include substituted and unsubstituted benzyl.
La referencia en la presente memoria a grupos heterocíclicos representa grupos que contienen uno o más de, pirrolilo, imidazolilo, pirazolilo, tiazolilo, isotiazolilo, oxazolilo, pirrolidinilo, pirrolinilo, imidazolidinilo, imidazolinilo, pirazolidinilo, tetrahidrofuranilo, piranilo, pironilo, piridilo, pirazinilo, piridazinilo, piperidilo, piperazinilo, morfolinilo, tionaftilo, benzofuranilo, isobenzofurilo, indolilo, oxiindolilo, isoindolilo, indazolilo, indolinilo, 7-azaindolilo, isoindazolilo, benzopiranilo, cumarinilo, isocumarinilo, quinolilo, isoquinolilo, naftiridinilo, cinolinilo, quinazolinilo, piridopiridilo, benzoxazinilo, quinoxadinilo, cromenilo, cromanilo, isocromanilo y carbolinilo.The reference herein to groups heterocyclic represents groups containing one or more of, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pironyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocumarinyl, quinolyl, isoquinolyl, naphthyridinyl, cinolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl, isochromanyl and carbolinyl
Las referencias en la presente memoria a grupos policíclicos representan un grupo que comprende dos o más anillos carbocíclicos o heterocíclicos no aromáticos que pueden estar a su vez sustituidos.References herein to groups polycyclics represent a group comprising two or more rings carbocyclic or non-aromatic heterocyclics that may be at your once replaced.
La referencia en la presente memoria a halógeno representa un radical flúor, cloro, bromo o yodo, preferiblemente un radical flúor o cloro.The reference herein to halogen represents a fluorine, chlorine, bromine or iodine radical, preferably a fluorine or chlorine radical.
El grupo Ar comprende un grupo arilo sustituido o no sustituido, donde el término "grupo arilo" y la posible sustitución de dicho grupo se definen como antes. Preferiblemente, Ar es un grupo fenilo sustituido o no sustituido. Los sustituyente particularmente preferidos son los grupos eliminables de elección tales como halógenos (preferiblemente cloro o flúor), grupos trihalometilo (preferiblemente trifluorometilo), ciano y nitro. Preferiblemente, Ar es fenilo, 3,5-diclorofenilo, p-trifluorometilfenilo, p-cianofenilo, o p-nitrofenilo.The Ar group comprises a substituted or unsubstituted aryl group, where the term "aryl group" and the possible substitution of said group are defined as before. Preferably, Ar is a substituted or unsubstituted phenyl group. Particularly preferred substituents are the removable groups of choice such as halogens (preferably chlorine or fluorine), trihalomethyl (preferably trifluoromethyl), cyano and nitro groups. Preferably, Ar is phenyl, 3,5-dichlorophenyl, p- trifluoromethylphenyl, p- cyanophenyl, or p- nitrophenyl.
Y puede ser oxígeno o azufre. Preferiblemente, Y es oxígeno.And it can be oxygen or sulfur. Preferably, Y It is oxygen.
X^{1} se selecciona entre O, NR^{3}, S,
CR^{3}R^{4}, CR^{3}W^{1} y CW^{1}W^{2} donde R^{3} y
R^{4} se seleccionan independientemente entre hidrógeno, grupos
alquilo y arilo; y W^{1} y W^{2} son heteroátomos.
Preferiblemente, X^{1} se selecciona entre O, S y NR^{3}.
Preferiblemente, X^{1} es NR^{3}. Cuando está presente, R^{3}
es preferiblemente H. Cuando están presentes, W^{1} y W^{2}
pueden comprender independientemente cualquier heteroátomo tal como
un halógeno, preferiblemente
flúor.X 1 is selected from O, NR 3, S, CR 3 R 4, CR 3 W 1 and CW 1 W 2 where R 3 and R 4 are independently selected from hydrogen, alkyl and aryl groups; and W1 and W2 are heteroatoms. Preferably, X 1 is selected from O, S and NR 3. Preferably, X 1 is NR 3. When present, R 3 is preferably H. When present, W 1 and W 2 can independently comprise any heteroatom such as a halogen, preferably
fluorine.
X^{6} es CH_{2}, y X^{2} se selecciona (independientemente de X^{1}) entre O, NR^{3}, S, CR^{3}R^{4}, CR^{3}W^{1} y CW^{1}W^{2} donde R^{3} y R^{4} se seleccionan independientemente entre H, grupos alquilo y arilo; y W^{1} y W^{2} son heteroátomos. Cuando está presente, X^{2} es preferiblemente oxígeno. Cuando está presente, R^{3} es preferiblemente H. Cuando están presentes W^{1} y W^{2} comprenden independientemente cualquier heteroátomo tal como halógeno, preferiblemente flúor.X 6 is CH 2, and X 2 is selected (independently of X 1) between O, NR 3, S, CR 3 R 4, CR 3 W 1 and CW 1 W 2 where R 3 and R 4 are independently selected from H, alkyl groups and aryl; and W1 and W2 are heteroatoms. When present, X 2 is preferably oxygen. When present, R3 it is preferably H. When W 1 and W 2 are present independently comprise any heteroatom such as halogen, preferably fluorine.
X^{4} es oxígeno.X 4 is oxygen.
X^{5} puede estar ausente o es CH_{2}.X 5 may be absent or is CH 2.
Z puede comprender O o NR^{5}, donde R^{5} se selecciona entre H, grupos alquilo y arilo. Preferiblemente, Z es O o NR^{5}. Preferiblemente, R^{5} es hidrógeno. Muy preferiblemente, Z es oxígeno.Z may comprise O or NR 5, where R 5 is Select between H, alkyl and aryl groups. Preferably, Z is O or NR5. Preferably, R 5 is hydrogen. Very preferably, Z is oxygen.
J es un grupo alquilo sustituido o no sustituido. Preferiblemente, J es un grupo alquilo C_{1}-C_{6} sustituido o no sustituido, preferiblemente un grupo bencilo o metilo.J is a substituted or unsubstituted alkyl group. Preferably, J is an alkyl group C 1 -C 6 substituted or unsubstituted, preferably a benzyl or methyl group.
X^{3} es un grupo CR^{1}R^{2} donde R^{1} y R^{2} se seleccionan independientemente entre hidrógeno, grupos alquilo y arilo. Preferiblemente, al menos uno de R^{1} y R^{2} es hidrógeno. Se apreciará que si R^{1} y R^{2} son diferentes, el átomo de carbono al cual están unidos es un centro asimétrico. La estereoquímica en este sitio puede ser R o S o mixta. Cuando uno de R^{3} y R^{4} es hidrógeno, la estereoquímica es preferiblemente S.X 3 is a CR 1 R 2 group where R 1 and R2 are independently selected from hydrogen, groups alkyl and aryl. Preferably, at least one of R1 and R2 It is hydrogen. It will be appreciated that if R 1 and R 2 are different, The carbon atom to which they are attached is an asymmetric center. The stereochemistry on this site can be R or S or mixed. When one of R 3 and R 4 is hydrogen, the stereochemistry is preferably S.
Q se selecciona entre O, NR^{6}, S, CR^{6}R^{7}, CR^{6}W^{3} y CW^{3}W^{4}, donde R^{6} y R^{7} se seleccionan independientemente entre hidrógeno, grupos alquilo y arilo; y W^{2} y W^{3} son heteroátomos tales como átomos de halógeno, preferiblemente flúor. Preferiblemente, Q es O, S, CH_{2} o CF_{2}. Muy preferiblemente, Q es oxígeno.Q is selected from O, NR 6, S, CR 6 R 7, CR 6 W 3 and CW 3 W 4, where R 6 and R 7 are independently selected from hydrogen, groups alkyl and aryl; and W 2 and W 3 are heteroatoms such as halogen atoms, preferably fluorine. Preferably, Q is O, S, CH2 or CF2. Most preferably, Q is oxygen.
T^{1} y T^{2} están ligados entre sí y forman juntos el grupo:T1 and T2 are linked together and form together the group:
B comprende una base de purina o pirimidina, tal como adenina, timina, uracilo, citosina o guanina y derivados de las mismas. Entre los derivados de las mismas se incluyen bases de purina o pirimidina sustituidas donde los sustituyentes se definen como antes. Entre los ejemplos de las bases sustituidas se incluyen la pirimidina sustituida en posición 5. Preferiblemente B es adenina o timina.B comprises a purine or pyrimidine base, such such as adenine, thymine, uracil, cytosine or guanine and derivatives of the same. Derivatives thereof include bases of substituted purine or pyrimidine where the substituents are defined like before. Examples of substituted bases include the substituted pyrimidine in position 5. Preferably B is adenine or thymine.
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Preferiblemente, la presente invención proporciona un compuesto de fórmula (2)Preferably, the present invention provides a compound of formula (2)
donde Ar, R^{1}, J, X^{2}, X^{5}, X^{6}, Q, T^{1}, T^{2} y B se definen como antes; o un derivado o metabolito del mismo farmacéuticamente aceptable.where Ar, R1, J, X2, X 5, X 6, Q, T 1, T 2 and B are defined as before; or a derivative or metabolite thereof pharmaceutically acceptable.
Se apreciará que el grupo -NH-CHR^{1}-CO_{2}J corresponde a un \alpha-aminoácido con el grupo carboxi protegido. Preferiblemente, el grupo R^{1} corresponde a la cadena lateral de un aminoácido de origen natural tal como Alanina, Arginina, Asparragina, Acido aspártico, Cisteína, Cistina, Glicina, Acido glutámico, Glutamina, Histidina, Isoleucina, Leucina, Lisina, Metionina, Fenilalanina, Prolina, Serina, Treonina, Triptófano, Tirosina, Valina. Preferiblemente, R^{1} es Me o PhCH_{2} correspondiente a la cadena lateral de la alanina o la fenilalanina, respectivamente. Preferiblemente, la estereoquímica en el centro asimétrico -CHR^{1}- asimétrico corresponde a un L-aminoácido.It will be appreciated that the group -NH-CHR 1 -CO 2 J corresponds to an α-amino acid with the protected carboxy group. Preferably, the R 1 group corresponds to the side chain of a naturally occurring amino acid such as Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Cystine, Glycine, Glutamic acid, Glutamine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine. Preferably, R 1 is Me or PhCH 2 corresponding to the side chain of alanine or phenylalanine, respectively. Preferably, the stereochemistry at the asymmetric center -CHR1-asymmetric corresponds to an L- amino acid.
Según una realización preferida, la presente invención proporciona un compuesto de fórmula (3):According to a preferred embodiment, the present Invention provides a compound of formula (3):
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donde Ar, Y, X^{1}, X^{2}, X^{3}, X^{4}, Z, Q y B se definen como antes.where Ar, Y, X 1, X 2, X 3, X 4, Z, Q and B are defined as before.
Más preferiblemente, la invención proporciona un compuesto según la fórmula (3), de fórmula (4):More preferably, the invention provides a compound according to formula (3), of formula (4):
donde Ar, R^{1} y J se definen como antes; o un derivado o metabolito farmacéuticamente aceptable del mismo. Preferiblemente, la invención proporciona un compuesto de fórmula (4) en el que Ar, R^{1} y J se definen según la Tabla 1.where Ar, R1 and J are defined like before; or a pharmaceutically acceptable derivative or metabolite of the same. Preferably, the invention provides a compound of formula (4) in which Ar, R1 and J are defined according to the Table one.
Una característica de los compuestos éster arílico de fosfato (1) de la presente invención es que muestran una eficacia anti-viral significativamente intensificada, tanto en ensayos in vitro como in vivo, en comparación con su correspondiente análogo nucleosídico (9)A characteristic of the aryl ester phosphate compounds (1) of the present invention is that they show significantly enhanced anti-viral efficacy, both in vitro and in vivo assays , compared to their corresponding nucleoside analogue (9)
Además, los compuestos de la presente invención muestran una toxicidad significativamente reducida en comparación con sus correspondientes análogos (9).In addition, the compounds of the present invention show a significantly reduced toxicity compared with their corresponding analogues (9).
Los compuestos de la presente invención muestran por tanto un índice de selectividad enormemente intensificado (razón de CC_{50} (toxicidad): CE_{50} (actividad)) en comparación con su correspondiente análogo nucleosídico.The compounds of the present invention show therefore a highly intensified selectivity index (reason of CC 50 (toxicity): EC 50 (activity)) compared to its corresponding nucleoside analog.
Los experimentos con compuestos radiomarcados de la presente invención han demostrado que los compuestos producen niveles intracelulares intensificados de nucleósidos 5'-trifosfato, siendo la intensificación particularmente significativa en las células TK^{-}. De ese modo, los compuestos de la presente invención pueden actuar en parte mediante la ruta metabólica conocida.Experiments with radiolabeled compounds of the present invention have shown that the compounds produce intensified intracellular levels of nucleosides 5'-triphosphate, being the intensification particularly significant in TK - cells. That way, the compounds of the present invention may act in part through the known metabolic pathway.
Sin embargo, se ha descubierto que los compuestos de la presente invención muestran una actividad sorprendente frente a las cepas resistentes a los nucleósidos de VIH. Esto indica que los compuestos de la presente invención también actúan mediante una ruta independiente de un metabolito 5'-trifosfato.However, it has been discovered that the compounds of the present invention show a surprising activity against to HIV-resistant nucleoside strains. This indicates that the compounds of the present invention also act by a independent path of a metabolite 5'-triphosphate.
Se ha demostrado que los compuestos de la presente invención conducen a la generación intracelular de elevados niveles de un metabolito (10).It has been shown that the compounds of the present invention lead to the intracellular generation of elevated levels of a metabolite (10).
El metabolito (10) también puede ser preparado mediante tratamiento del correspondiente compuesto según la fórmula (1) con esterasa de hígado de cerdo. Por otra parte, se ha demostrado que los compuestos de fórmula (10) son inhibidores directos de la transcriptasa inversa de VIH.The metabolite (10) can also be prepared by treatment of the corresponding compound according to the formula (1) with pig liver esterase. On the other hand, it has shown that the compounds of formula (10) are inhibitors Direct HIV reverse transcriptase.
Según un aspecto adicional de la presente invención se proporciona un compuesto de fórmula (10)According to an additional aspect of the present invention is provided a compound of formula (10)
donde Ar, Y, X^{1}, X^{2}, X^{3}, X^{4}, X^{6}, T^{1}, T^{2}, Q, X^{5} y B se definen como antes, o un derivado o metabolito farmacéuticamente aceptable del mismo.where Ar, Y, X 1, X 2, X 3, X 4, X 6, T 1, T 2, Q, X 5 and B are defined as before, or a pharmaceutically derived or metabolite acceptable from same.
La generación intracelular de metabolitos anti-virales tales como (10) es una importante característica de la invención por numerosas razones. En primer lugar, la actividad directa de (10) sobre RT elimina la necesidad de fosforilación mediada por nucleótido-quinasa adicional, que puede ser lenta en muchos casos. En los casos en los que el nucleósido fosfato no es un sustrato para las nucleótido quinasas del huésped, la activación será escasa y la eficacia anti-viral baja, incluso si el trifosfato es un excelente inhibidor de RT. En tales casos, la generación de metabolitos tales como (10) puede conducir a un aumento muy significativo de la acción antiviral. Tales compuestos pueden actuar directamente por propio derecho o por medio de un producto de transposición, descomposición o desproporción o por medio de un contaminante. Por otra parte, la estructura de metabolitos tales como (10) puede ser diseñada adicionalmente para optimizar la unión a la estructura conocida de la RT, y semejantes metabolitos modificados podrían ser liberados intracelularmente utilizando la tecnología descrita aquí, para intensificar adicionalmente el efecto anti-viral.The intracellular generation of metabolites anti-virals such as (10) is an important characteristic of the invention for numerous reasons. In first instead, the direct activity of (10) on RT eliminates the need for nucleotide kinase mediated phosphorylation additional, which can be slow in many cases. In cases in that the nucleoside phosphate is not a substrate for nucleotides host kinases, activation will be poor and efficacy low anti-viral, even if triphosphate is a excellent RT inhibitor. In such cases, the generation of metabolites such as (10) can lead to a very high increase significant antiviral action. Such compounds can act directly in its own right or through a product of transposition, decomposition or disproportion or by means of a pollutant. Moreover, the structure of such metabolites as (10) it can be additionally designed to optimize the joint to the known structure of RT, and similar metabolites modified could be released intracellularly using the technology described here, to further intensify the effect anti-viral
Por "derivado farmacéuticamente aceptable" se representa cualquier sal, éster o sal de semejante éster farmacéuticamente aceptable o cualquier otro compuesto que tras la administración a un receptor sea capaz de proporcionar (directa o indirectamente) un compuesto de fórmula (1) o (10). Por "metabolito farmacéuticamente aceptable" se representa un metabolito o resto de un compuesto de fórmula (1) o (10) que origine un modo de inhibición de la transcriptasa inversa independiente de la resistencia a los nucleósidos o independiente del nucleósido 5'-trifosfato mostrado por los compuestos de fórmula (1) o (10).By "pharmaceutically acceptable derivative" any salt, ester or salt of such an ester is represented pharmaceutically acceptable or any other compound that after administration to a recipient be able to provide (direct or indirectly) a compound of formula (1) or (10). By "pharmaceutically acceptable metabolite" represents a metabolite or remainder of a compound of formula (1) or (10) that originates a reverse transcriptase inhibition mode independent of nucleoside resistance or nucleoside independent 5'-triphosphate shown by the compounds of formula (1) or (10).
Según un aspecto adicional de la presente invención se proporciona un compuesto según la presente invención para su uso en un método de tratamiento, preferiblemente en la profilaxis o el tratamiento de la infección viral.According to an additional aspect of the present invention a compound according to the present invention is provided for use in a treatment method, preferably in the prophylaxis or treatment of viral infection.
Según un aspecto adicional de la presente invención se proporciona el uso de un compuesto según la presente invención en la fabricación de un medicamento para la profilaxis o el tratamiento de la infección viral.According to an additional aspect of the present invention the use of a compound according to the present is provided invention in the manufacture of a medicament for prophylaxis or The treatment of viral infection.
Un compuesto según la presente invención puede ser empleado en un método de profilaxis o tratamiento de la infección viral que comprende la administración a un paciente que necesite semejante tratamiento de una dosis eficaz del compuesto.A compound according to the present invention can be employed in a method of prophylaxis or treatment of viral infection comprising administration to a patient who need such treatment of an effective dose of compound.
La infección viral puede comprender cualquier infección viral tal como VIH y herpes virus, incluyendo HSV 1 y HSV 2, CMV, VZV, EBV, HAV, HBV, HCV, HDV, papiloma, rabia e influenza.The viral infection can comprise any viral infection such as HIV and herpes virus, including HSV 1 and HSV 2, CMV, VZV, EBV, HAV, HBV, HCV, HDV, papilloma, rabies and influenza.
Preferiblemente, la infección viral comprende la infección por VIH, más preferiblemente VIH-I o VIH-II. Es una característica de la presente invención que los compuestos muestren una buena actividad tanto frente a VIH-I como VIH-II.Preferably, the viral infection comprises the HIV infection, more preferably HIV-I or HIV-II It is a feature of the present invention that the compounds show a good activity both against HIV-I as HIV-II.
Según un aspecto adicional de la presente invención se proporciona el uso de un compuesto de la presente invención en la fabricación de un medicamento para su uso en la inhibición de una transcriptasa inversa mediante un modo de acción independiente de la resistencia a nucleósidos o independiente del nucleósido 5'-trifosfato.According to an additional aspect of the present invention the use of a compound of the present is provided invention in the manufacture of a medicament for use in the inhibition of a reverse transcriptase through a mode of action independent of nucleoside resistance or independent of 5'-triphosphate nucleoside.
Según un aspecto adicional de la presente invención se proporciona una composición farmacéutica que comprende un compuesto de la presente invención combinado con un excipiente farmacéuticamente aceptable.According to an additional aspect of the present invention is provided a pharmaceutical composition comprising a compound of the present invention combined with an excipient pharmaceutically acceptable.
Según un aspecto adicional de la presente invención se proporciona un método de preparación de una composición farmacéutica que comprende la etapa de combinar un compuesto de la presente invención con un excipiente farmacéuticamente aceptable.According to an additional aspect of the present invention is provided a method of preparing a composition pharmaceutical comprising the step of combining a compound of the present invention with a pharmaceutically excipient acceptable.
Los medicamentos empleados en la presente invención pueden ser administrados mediante las rutas oral o parenteral, incluyendo la administración intravenosa, intramuscular, intraperitoneal, subcutánea, transdérmica, por vías altas (aerosoles), rectal, vaginal y tópica (incluyendo bucal y sublingual).The medications used herein invention can be administered by oral routes or parenteral, including intravenous, intramuscular administration, intraperitoneal, subcutaneous, transdermal, upstream (aerosols), rectal, vaginal and topical (including oral and sublingual)
Para la administración oral, los compuestos de la invención se proporcionarán generalmente en forma de tabletas o cápsulas, en forma de polvo o gránulos, o en forma de una solución o suspensión acuosa.For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules, in the form of powder or granules, or in the form of a solution or aqueous suspension
Entre las tabletas para uso oral se puede incluir el ingrediente activo mezclado con excipientes farmacéuticamente aceptables tales como diluyentes inertes, agentes disgregantes, agentes aglutinantes, agentes lubricantes, agentes edulcorantes, agentes aromatizantes, agentes colorantes y conservantes. Entre los diluyentes inertes adecuados se incluyen carbonato de sodio y calcio, fosfato de sodio y calcio, y lactosa, mientras el almidón de maíz y el ácido algínico son agentes disgregantes adecuados. Entre los agentes aglutinantes se pueden incluir almidón y gelatina, mientras el agente lubricante, si está presente, será generalmente estearato de magnesio, ácido esteárico o talco. Si se desea, las tabletas pueden ser recubiertas con un material tal como monoestearato de glicerilo o diestearato de glicerilo, para retrasar la absorción en el tracto gastrointestinal.Tablets for oral use may include the active ingredient mixed with pharmaceutically excipients acceptable such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Between the Suitable inert diluents include sodium carbonate and calcium, sodium phosphate and calcium, and lactose, while the starch of Corn and alginic acid are suitable disintegrating agents. Between the binding agents can include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets can be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay Absorption in the gastrointestinal tract.
Entre las cápsulas para la administración oral se incluyen cápsulas de gelatina dura en las cuales el ingrediente activo se mezcla con un diluyente inerte sólido, y cápsulas de gelatina blanda en las que el ingrediente activo se mezcla con agua o un aceite tal como aceite de cacahuete, parafina líquida o aceite de oliva.Among the capsules for oral administration are include hard gelatin capsules in which the ingredient active is mixed with a solid inert diluent, and capsules soft gelatin in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or oil made of olives.
Las formulaciones para la administración rectal pueden ser presentadas en forma de un supositorio con una base adecuada que comprende por ejemplo manteca de cacao o un salicilato.Formulations for rectal administration they can be presented in the form of a suppository with a base suitable comprising for example cocoa butter or a salicylate.
Las formulaciones adecuadas para la administración vaginal pueden ser presentadas en forma de pesarios, tampones, cremas, geles, pastas, espumas o formulaciones para pulverización conteniendo además del ingrediente activo portadores tales como los conocidos en la técnica por ser apropiados.The right formulations for Vaginal administration can be presented in the form of pessaries, buffers, creams, gels, pastes, foams or formulations for spray containing in addition to the active ingredient carriers such as those known in the art for being appropriate.
Para el uso intramuscular, intraperitoneal, subcutáneo e intravenoso, los compuestos de la invención se proporcionarán generalmente en soluciones o suspensiones acuosas estériles, tamponadas a un pH e isotonicidad apropiados. Entre los vehículos acuosos adecuados se incluyen solución de Ringer y cloruro de sodio isotónico. Entre las composiciones acuosas según la invención se pueden incluir agentes suspensores tales como derivados de celulosa, alginato de sodio, polivinilpirrolidona y goma de tragacanto, y un agente humectante tal como lecitina. Entre los conservantes adecuados para las suspensiones acuosas se incluyen p-hidroxibenzoato de etilo y n-propilo.For intramuscular, intraperitoneal use, subcutaneous and intravenous, the compounds of the invention are they will generally provide in aqueous solutions or suspensions sterile, buffered at an appropriate pH and isotonicity. Between the Suitable aqueous vehicles include Ringer's solution and chloride of isotonic sodium. Among the aqueous compositions according to the invention suspending agents such as derivatives may be included of cellulose, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Between the Suitable preservatives for aqueous suspensions are included ethyl p-hydroxybenzoate and n-propyl.
Los compuestos de la invención también se pueden presentar en forma de formulaciones de liposomas.The compounds of the invention can also be present in the form of liposome formulations.
En general una dosis adecuada estará en el intervalo de 0,1 a 300 mg por kilogramo de peso corporal del receptor por día, preferiblemente en el intervalo de 6 a 150 mg por kilogramo de peso corporal por día y muy preferiblemente en el intervalo de 15 a 100 mg por kilogramo de peso corporal por día. La dosis deseada se presenta preferiblemente en forma de dos, tres, cuatro, cinco o seis o más subdosis administradas a intervalos apropiados a lo largo de todo el día. Estas subdosis pueden ser administradas en formas de dosificación unitarias, por ejemplo, conteniendo 10 a 1500 mg, preferiblemente 20 a 1000 mg, y muy preferiblemente de 50 a 700 mg de ingrediente activo por forma unitaria de dosificación.In general an adequate dose will be in the range of 0.1 to 300 mg per kilogram of body weight of the receptor per day, preferably in the range of 6 to 150 mg per kilogram of body weight per day and most preferably in the range of 15 to 100 mg per kilogram of body weight per day. The Desired dose is preferably presented in the form of two, three, four, five or six or more sub-doses administered at intervals appropriate throughout the day. These subdoses can be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and very preferably 50 to 700 mg of active ingredient per form unit dosage.
Según un aspecto adicional de la presente invención se proporciona un procedimiento para la preparación de un compuesto según la presente invención, comprendiendo el procedimiento la reacción de un compuesto de fórmula (11)According to an additional aspect of the present invention is provided a process for the preparation of a compound according to the present invention, the process the reaction of a compound of formula (11)
con un compuesto de fórmula(12)with a compound of formula (12)
La reacción se puede llevar a cabo en tetrahidrofurano en presencia de N-metilimidazol.The reaction can be carried out in tetrahydrofuran in the presence of N-methylimidazole
A continuación se describirá la invención con referencia a las siguientes Figuras y Ejemplos. Se apreciará que lo que sigue es sólo a modo de ejemplo y que se pueden realizar modificaciones a detallar mientras se encuentren todavía dentro del alcance de la invención.The invention will now be described with reference to the following Figures and Examples. It will be appreciated that that follows is only by way of example and that can be done modifications to detail while still within the scope of the invention.
La Figura 1 ilustra la actividad antiviral in vivo de d4T (comparativa) y el compuesto éster arílico de fosforamidato de 324 en ratones infectados con MSV. Las dosis de fármaco son 50 [baja] o 200 [alta] mg/kg/día administrado i.p. durante 4 días empezando 1 hora antes de la inoculación con MSV.Figure 1 illustrates the in vivo antiviral activity of d4T (comparative) and the aryl ester phosphoramidate compound of 324 in MSV infected mice. The drug doses are 50 [low] or 200 [high] mg / kg / day administered ip for 4 days starting 1 hour before inoculation with MSV.
Todos los experimentos que implicaban compuestos sensibles al agua fueron llevados a cabo en condiciones escrupulosamente secas. El tetrahidrofurano fue secado calentando a reflujo sobre sodio y benzofenona seguido de destilación y almacenamiento sobre tamices activos. El N-metilimidazol se purificó mediante destilación. Los nucleósidos se secaron a una temperatura elevada a vacío sobre P_{2}O_{5}. Se registraron los espectros de Resonancia Magnética Nuclear de protón, carbono y fósforo (rmn H^{1}, C^{13}, P^{31}) en un espectrómetro Bruker Avance DPX que funcionaba a 300 MHz, 75,5 MHz, y 121,5 MHz respectivamente. Todos los espectros de rmn fueron registrados en CDCl_{3} a la temperatura ambiente (20ºC +/-3ºC). Los desplazamientos químicos de H^{1} y C^{13} fueron expresados en partes por millón bajo campo de tetrametilsilano. Los valores de J hacen referencia a las constantes de acoplamiento y los patrones de desintegración de la señal se describen como singlete (s), singlete ancho (s ancho), doblete (d), triplete (t), cuartete (c), multiplete (m) o combinaciones de los mismos. Los desplazamientos químicos de P^{31} se expresan en partes por millón en relación con un patrón de ácido fosfórico externo. Muchos picos del RMN fueron desintegrados adicionalmente debido a la presencia de diastereoisómeros en el centro fosfato [quiral]. La cromatografía hace referencia a la cromatografía en columna instantánea y se llevó a cabo utilizando gel de sílice de Merck 60H (40-60 m, malla 230-400) como fase estacionaria. La cromatografía en capa fina se realizó utilizando placas de del de sílice con el reverso de aluminio Alugram SIL G/UV_{254}.All experiments involving water sensitive compounds were carried out under scrupulously dry conditions. Tetrahydrofuran was dried by heating under reflux over sodium and benzophenone followed by distillation and storage on active sieves. The N-methylimidazole was purified by distillation. The nucleosides were dried at an elevated temperature in vacuo over P2O5. The proton, carbon and phosphorus Nuclear Magnetic Resonance spectra (rmn H 1, C 13, P 31) were recorded on a Bruker Avance DPX spectrometer operating at 300 MHz, 75.5 MHz , and 121.5 MHz respectively. All rmn spectra were recorded in CDCl3 at room temperature (20 ° C +/- 3 ° C). The chemical shifts of H 1 and C 13 were expressed in parts per million under the tetramethylsilane field. The values of J refer to the coupling constants and the signal decay patterns are described as singlet (s), singlet width (s width), doublet (d), triplet (t), quartet (c), multiplet (m) or combinations thereof. The chemical shifts of P31 are expressed in parts per million in relation to an external phosphoric acid pattern. Many NMR peaks were further disintegrated due to the presence of diastereoisomers in the [chiral] phosphate center. Chromatography refers to flash column chromatography and was carried out using Merck 60H silica gel (40-60 m, 230-400 mesh) as the stationary phase. Thin layer chromatography was performed using silica plates with the aluminum back Alugram SIL G / UV 254.
Los espectros de masas se registraron mediante el modo de bombardeo de átomos rápido (FAB) en un espectrómetro VG 70- -250. Los datos de la HPLC se registraron utilizando un sistema cuaternario ACS con una columna ODS5 y un eluyente de agua/acetonitrilo, con 0-10 mm de agua al 82%, y después un gradiente lineal de agua al 20% durante 30 min, con una velocidad de flujo de 2 ml/min y detección mediante UV a 265 nm.Mass spectra were recorded by fast atom bombardment mode (FAB) on a VG spectrometer 70- -250. HPLC data was recorded using a ACS quaternary system with an ODS5 column and an eluent of water / acetonitrile, with 0-10 mm of 82% water, and then a linear gradient of 20% water for 30 min, with a flow rate of 2 ml / min and UV detection at 265 nm.
Los compuestos de ensayo fueron aislados en forma de mezclas de diastereoisómeros, surgiendo esta isomería de la estereoquímica mixta en el centro de fosfato. Los aceites resultantes no daban datos microanalíticos útiles pero se encontró que eran puros mediante espectroscopia RMN multinuclear de alto campo y análisis mediante HPLC riguroso.Test compounds were isolated in form of mixtures of diastereoisomers, this isomerism arising from the mixed stereochemistry in the phosphate center. Oils resulting did not give useful microanalytical data but it was found that were pure by high multinuclear NMR spectroscopy field and analysis by rigorous HPLC.
Los compuestos de la presente invención fueron preparados según los siguientes procedimientos generales.The compounds of the present invention were prepared according to the following general procedures.
Una solución del fenol apropiado (30,4 mmoles) y trietilamina (4,25 ml, 30,5 mmoles) en CH_{2}Cl_{2} seco (25 ml) se añadió a una solución de POCl_{3} recién destilado (10 ml, 107 mmoles) en CH_{2}Cl_{2} (30 ml) a -50ºC y la mezcla se agitó a la temperatura ambiente durante la noche. La mezcla de reacción se filtró y el producto filtrado se evaporó. Se añadió éter (20 ml) y el producto precipitado se filtró de nuevo. Tras la evaporación el residuo se destilaba si era posible.A solution of the appropriate phenol (30.4 mmol) and triethylamine (4.25 ml, 30.5 mmol) in dry CH2Cl2 (25 ml) was added to a solution of freshly distilled POCl3 (10 ml, 107 mmol) in CH 2 Cl 2 (30 ml) at -50 ° C and the mixture was stirred at the room temperature overnight. The reaction mixture is filtered and the filtrate was evaporated. Ether (20 ml) was added and The precipitated product was filtered again. After evaporation the residue was distilled if possible.
Una solución de trietilamina (1 ml - 7,17 mmoles)
en 15 ml de CH_{2}Cl_{2} seco se añadió gota a gota a una mezcla
de fenil fosforodicloridato (757,4 mg, 3,59 mmoles) e hidrocloruro
de éster metílico de L-alanina (500 mg, 3,58 mmoles)
en 50 ml de CH_{2}Cl_{2} seco a -80ºC en una hora. Después la
mezcla se agitó vigorosamente a -50ºC durante cinco horas y se
evaporó el CH_{2}Cl_{2}. Se añadieron 25 ml de éter seco y el
producto precipitado se separó por filtración en nitrógeno. La
evaporación del éter dio un aceite incoloro que se utilizó sin
purificación adicional para la siguiente
etapa.A solution of triethylamine (1 ml - 7.17 mmol) in 15 ml of dry CH2Cl2 was added dropwise to a mixture of phenyl phosphorodichloridate (757.4 mg, 3.59 mmol) and hydrochloride of L-alanine methyl ester (500 mg, 3.58 mmol) in 50 ml of dry CH 2 Cl 2 at -80 ° C in one hour. The mixture was then stirred vigorously at -50 ° C for five hours and the CH2Cl2 was evaporated. 25 ml of dry ether was added and the precipitated product was filtered off under nitrogen. Evaporation of the ether gave a colorless oil that was used without further purification for the next
stage.
Se añadió fenil N-metilalaninil fosforocloridato (250 mg, 0,9 mmoles, 2,0 equiv.) a una solución agitada de análogo de nucleósido 0,45 mmoles) y N-metilimidazol (0,37 ml, 143,5 \mul, 1,8 mmoles, 4 equiv.) en THF (2 ml). Al cabo de 4 horas, el disolvente se separó a presión reducida. La goma se disolvió en cloroformo (10 ml), y se lavó con HCl 1M (8 ml), bicarbonato de sodio (10 ml) y agua (15 ml). La fase orgánica se secó, y el disolvente se separó a vacío. El residuo se purificó mediante cromatografía sobre sílice eluyendo con cloroformo-metanol (97:3). La reunión y la evaporación del disolvente dieron el producto en forma de un sólido de color blanco.Phenyl N-methylalaninyl was added phosphorochloridate (250 mg, 0.9 mmol, 2.0 equiv.) to a solution agitated nucleoside analog 0.45 mmol) and N-methylimidazole (0.37 ml, 143.5 µL, 1.8 mmol, 4 equiv.) In THF (2 ml). After 4 hours, the solvent was removed under reduced pressure. The gum was dissolved in chloroform (10 ml), and was washed with 1M HCl (8 ml), sodium bicarbonate (10 ml) and water (15 ml). The organic phase was dried, and the solvent was removed in vacuo. He residue was purified by chromatography on silica eluting with chloroform-methanol (97: 3). The meeting and the evaporation of the solvent gave the product as a solid White color.
Rendimiento = 79%Yield = 79%
P^{31} (CDCl_{3}): 3,43 ppmP 31 (CDCl 3): 3.43 ppm
H^{1} (CDCl_{3}): 9,25 (0,5H, s, B, NH), 9,23 (0,5H, s, A, NH), 7,34 (0,5H, s, 11-6, B), 7,33 (0,5H, s, H-6, A), 7,14-7,00 (5H, m, Ph, H-1'), 6,28 (1H, m, H-3'), 5,88 (1H, m, H-2'), 5,00 (1H, m, H-4'), 4,38-4,25 (2H, m, H-5'), 3,93 (2H, m, ala-NH, ala-CH), 3,70 (1,5H, s, OMe, A), 3,67 (1,5H, s, OMe, B), 2,60 (2H, c, CH_{2}CH_{3}, J=7,5 Hz), 1,84 (1,5H, d, 5-CH_{3}, J=1,2 Hz), 1,80 (1,5H, d, 5-CH_{3}, J=1,2 Hz), 1,31 (3H, m, CH_{2}CH_{3}, 1,19 (3H, m, ala-CH_{3}).H 1 (CDCl 3): 9.25 (0.5H, s, B, NH), 9.23 (0.5H, s, A, NH), 7.34 (0.5H, s, 11-6, B), 7.33 (0.5H, s, H-6, A), 7.14-7.00 (5H, m, Ph, H-1 '), 6.28 (1H, m, H-3'), 5.88 (1H, m, H-2 '), 5.00 (1H, m, H-4'), 4.38-4.25 (2H, m, H-5 '), 3.93 (2H, m, NH-wing, CH-wing), 3.70 (1.5H, s, OMe, A), 3.67 (1.5H, s, OMe, B), 2.60 (2H, c, CH2CH3, J = 7.5 Hz), 1.84 (1.5H, d, 5-CH 3, J = 1.2 Hz), 1.80 (1.5H, d, 5-CH3, J = 1.2 Hz), 1.31 (3H, m, CH 2 CH 3, 1.19 (3H, m, ala-CH 3).
C^{13} (CDCl_{3}): 174,25 (ala-CO, A), 174,12 (ala-CO, B), 164,22 (C-4, B), 164,17 (C-4, A), 151,15 (C-2, B), 151,12 (C-2, A), 148,29 (i-Ph, B), 148,16 (i-Ph, A), 141,24 (p-Ph, A), 141,19 (p-Ph, B), 136,06 (C-6, B), 135,76 (C-6, A), 133,50 (C-3', A), 133,15 (C-3', B), 129,11 (o-Ph, A), 129,05 (o-Ph, B), 127,54 (C-2', A), 127,36 (C-2', B), 120,08 (d, m-Ph, B, J=3,9 Hz), 119,90 (d, m-Ph, A, J=4,9 Hz), 111,51 (C-5, A), 111,40 (C-5, B), 89,83 (C-1', B), 89,60 (C-1', A), 84,88 (d, C-4', B, J=8,8 Hz), 84,70 (d, C-4', A, J=8,8 Hz), 67,11 (d, C-5', A, J=4,9 Hz), 66,48 (d, C-5', B, J=4,9 Hz), 52,65 (OMe), 50,26 (ala-CH, B), 50,13 (ala-CH, A), 28,19 (Ph-CH_{2}), 20,97 (d, ala-CH_{3}, B, J=4,9 Hz), 20,90 (d, ala-CH_{3}, A, J=4,9 Hz), 15,69 (Ph-CH_{2}CH_{3}), 12,45 (5-CH_{3}, A), 12,41 (5-CH_{3}, B).C 13 (CDCl 3): 174.25 (wing-CO, A), 174.12 (wing-CO, B), 164.22 (C-4, B), 164.17 (C-4, A), 151.15 (C-2, B), 151.12 (C-2, A), 148.29 (i-Ph, B), 148.16 (i-Ph, A), 141.24 (p-Ph, A), 141.19 (p-Ph, B), 136.06 (C-6, B), 135.76 (C-6, A), 133.50 (C-3 ', A), 133.15 (C-3', B), 129.11 (o-Ph, A), 129.05 (o-Ph, B), 127.54 (C-2 ', A), 127.36 (C-2', B), 120.08 (d, m-Ph, B, J = 3.9 Hz), 119.90 (d, m-Ph, A, J = 4.9 Hz), 111.51 (C-5, A), 111.40 (C-5, B), 89.83 (C-1 ', B), 89.60 (C-1 ', A), 84.88 (d, C-4', B, J = 8.8 Hz), 84.70 (d, C-4 ', A, J = 8.8 Hz), 67.11 (d, C-5 ', A, J = 4.9 Hz), 66.48 (d, C-5', B, J = 4.9 Hz), 52.65 (OMe), 50.26 (wing-CH, B), 50.13 (ala-CH, A), 28.19 (Ph-CH2), 20.97 (d, ala-CH 3, B, J = 4.9 Hz), 20.90 (d, ala-CH 3, A, J = 4.9 Hz), 15.69 (Ph-CH 2 CH 3), 12.45 (5-CH 3, A), 12.41 (5-CH 3, B).
MS: C_{22}H_{29}N_{3}O_{8}P: 494 (MH^{+}, 5), 368 (MH^{+}-timina, 25), 228MS: C 22 H 29 N 3 O 8 P: 494 (MH <+>, 5), 368 (MH <+> - thymine, 25), 228
(15), 81 (C_{5}H_{5}O, pico base) Masa exacta: esperada 494,1692; encontrada 494,1693(15), 81 (C 5 H 5 O, base peak) Mass exact: expected 494.1692; found 494.1693
HLC: RT = 27,23 y 27,48 minHLC: RT = 27.23 and 27.48 min
Rendimiento = 88%Yield = 88%
P^{31} (CDCl_{3}): 3,20 y 3,86 ppmP 31 (CDCl 3): 3.20 and 3.86 ppm
H^{1} (CDCl_{3}): 1,32 y 1,34 (d, 3H, J=6,8Hz, CH_{3} ala); 1,81 y 1,84 (d, 3H, 5CH_{3}); 3,69 y 3,70 (s, 3H, OMe); 3,84-4,00 (m, 2H, CH ala + NH ala); 4,32 (m, 2H, H5'); 5,02 (m, 1H, H4'); 5,88 (m, 1H, H2'); 6,33 (m, 1H, H3'); 7,03 (m, 1H, H1'); 7,15-7,35 (m, 6H, Ar + H6); 9,22 y 9,26 (s ancho, 1H, NH)H 1 (CDCl 3): 1.32 and 1.34 (d, 3H, J = 6.8Hz, CH 3 wing); 1.81 and 1.84 (d, 3H, 5CH3); 3.69 and 3.70 (s, 3H, OMe); 3.84-4.00 (m, 2H, CH wing + NH wing); 4.32 (m, 2H, H5 '); 5.02 (m, 1H, H4 '); 5.88 (m, 1H, H2 '); 6.33 (m, 1H, H3 '); 7.03 (m, 1H, H1 '); 7.15-7.35 (m, 6H, Ar + H6); 9.22 and 9.26 (wide s, 1H, NH)
C^{13} (CDCl_{3}): 12,52 (5CH_{3}); 21,02 (CH_{3} ala); 50,22-50,35 (CH ala); 52,74 COMe); 66,62-67,29 (C5'); 84,80-84,88 (C4'); 89,69-89,93 (C1'); 111,44-111,57 (C5); 120,13-120,31 (Ar orto); 125,30 (Ar para); 127,49-127,65 (02'); 129,87-129,93 (Ar meta); 133,19-133,50 (C3'); 135,77-136,06 (C6); 150,51 (Ar ipso); 151,16 (C2); 164,14 (C4); 174,12 (Co ala)C 13 (CDCl 3): 12.52 (5CH 3); 21.02 (CH 3 wing); 50.22-50.35 (CH wing); 52.74 COMe); 66.62-67.29 (C5 '); 84.80-84.88 (C4 '); 89.69-89.93 (C1 '); 111.44-111.57 (C5); 120.13-120.31 (Ar ortho); 125.30 (Ar for); 127.49-127.65 (02 '); 129.87-129.93 (Ar meta); 133.19-133.50 (C3 '); 135.77-136.06 (C6); 150.51 (Ar ipso); 151.16 (C2); 164.14 (C4); 174.12 (Co to)
MS: 466 (MH^{+0}, 7) 340 (MH^{+0}-base); 200 (17); 136 (47); 89 (25); 81 (C_{5}H_{5}O, pico base)MS: 466 (MH + 0, 7) 340 (MH + 0 -base); 200 (17); 136 (47); 89 (25); 81 (C 5 H 5 O, base peak)
HPLC: RT = 22,48 y 22,87 minHPLC: RT = 22.48 and 22.87 min
Rendimiento = 89%Yield = 89%
P^{31} (CDCl_{3}): 3,16 ppmP 31 (CDCl 3): 3.16 ppm
H^{1} (CDCl_{3}): 9,75 (1H, s, NH), 7,24 (0,5H, d, H-6, B, J=1,2 Hz), 7,17 (0,5H, d, H-6, A, J=1,2 Hz), 7,09 (5H, m, Ph, H-1'), 6,22 (1H, m, H-3'), 5,82 (1H, m, H-2'), 4,94 (1H, m, H-4'), 4,30-3,84 (4H, m, ala-NH, ala-CH, H-5'), 3,63 (1,5H, s, OMe, A), 3,62 (1,5H, s, OMe, B), 1,77 (1,5H, d, 5-CH_{3}, B, J=1,0 Hz), 1,74 (1,5H, d, 5-CH_{3}, A, J=1,0 Hz), 1,29 (1,5H, d, ala-CH_{3}, B, J=7,0 Hz), 1,23 (1,5H, d, ala-CH_{3}, A, J=7,0 Hz).H 1 (CDCl 3): 9.75 (1H, s, NH), 7.24 (0.5H, d, H-6, B, J = 1.2 Hz), 7.17 (0.5H, d, H-6, A, J = 1.2 Hz), 7.09 (5H, m, Ph, H-1 '), 6.22 (1H, m, H-3'), 5.82 (1H, m, H-2 '), 4.94 (1H, m, H-4'), 4.30-3.84 (4H, m, wing-NH, CH-wing, H-5 '), 3.63 (1.5H, s, OMe, A), 3.62 (1.5H, s, OMe, B), 1.77 (1.5H, d, 5-CH 3, B, J = 1.0 Hz), 1.74 (1.5H, d, 5-CH 3, A, J = 1.0 Hz), 1.29 (1.5H, d, ala-CH 3, B, J = 7.0 Hz), 1.23 (1.5H, d, ala-CH 3, A, J = 7.0 Hz).
C^{13} (CDCl_{3}): 174,19 (d, ala-CO, B, J=6,8 Hz), 174,00 (d, ala-CO, A, J=6,8 Hz), 164,25 (C-4, B), 164,20 (C-4, A), 159,77 (d, p-Ph, J=243,6 Hz), 151,14 (C-2), 146,25 (i-Ph), 125,99 (C-6, A), 135,70 (C-6, B), 133,40 (C-3', A), 133,05 (C-3', B), 127,61 (C-2', B), 127,45 (C-2', A), 121,70 (m, o-Ph), 116,37 (d, m-Ph, A, J=23,5 Hz), 116,34 (d, m-Ph, B, J=23,5 Hz), 111,45 (C-5, A), 111,32 (C-5, B), 89,87 (C-1', A), 89,63 (C-1', B), 84,66 (d, C-4', J=5,9 Hz), 67,29 (d, C-5', A, J=4,9 Hz), 66,10 (d, C-5', B, J=4,9 Hz), 52,70 (OMe), 50,26 (ala-CH, A), 50,13 (ala-CH, B), 20,92 (d, ala-CH_{3}, A, J=4,8 Hz), 20,88 (d, ala-CH_{3}, B, J=4,8 Hz), 12,45 (5-CH_{3}, B), 12,41 (5-CH_{3}, A).C 13 (CDCl 3): 174.19 (d, wing-CO, B, J = 6.8 Hz), 174.00 (d, wing-CO, A, J = 6.8 Hz), 164.25 (C-4, B), 164.20 (C-4, A), 159.77 (d, p-Ph, J = 243.6 Hz), 151.14 (C-2), 146.25 (i-Ph), 125.99 (C-6, A), 135.70 (C-6, B), 133.40 (C-3 ', A), 133.05 (C-3 ', B), 127.61 (C-2', B), 127.45 (C-2 ', A), 121.70 (m, o-Ph), 116.37 (d, m-Ph, A, J = 23.5 Hz), 116.34 (d, m-Ph, B, J = 23.5 Hz), 111.45 (C-5, A), 111.32 (C-5, B), 89.87 (C-1 ', A), 89.63 (C-1 ', B), 84.66 (d, C-4', J = 5.9 Hz), 67.29 (d, C-5 ', A, J = 4.9 Hz), 66.10 (d, C-5 ', B, J = 4.9 Hz), 52.70 (OMe), 50.26 (wing-CH, A), 50.13 (wing-CH, B), 20.92 (d, ala-CH 3, A, J = 4.8 Hz), 20.88 (d, ala-CH 3, B, J = 4.8 Hz), 12.45 (5-CH 3, B), 12.41 (5-CH 3, TO).
MS: C_{20}H_{24}N_{3}O_{8}PF: 484 (MH^{+}, 11), 358 (MH^{+}-timina, 20), 218 (13), 154 (32), 136 (28), 81 (C_{5}H_{5}O, pico base). Masa exacta: esperada 484,1285; encontrada 484,1318MS: C 20 H 24 N 3 O 8 PF: 484 (MH +, 11), 358 (MH + - thymine, 20), 218 (13), 154 (32), 136 (28), 81 (C 5 H 5 O, base peak). Mass exact: expected 484,1285; found 484.1318
HPLC: RT = 25,17 y 25,40 minHPLC: RT = 25.17 and 25.40 min
Rendimiento = 80%Yield = 80%
P^{31} (CDCl_{3}): 2,49 y 3,16 ppmP 31 (CDCl 3): 2.49 and 3.16 ppm
H^{1} (CDCl_{3}): 9,06 (1H, s, NH), 7,45 (5H, m, H-6, Ph), 7,03 (1H, m, H-1'), 6,31 (1H, m, H-3'), 5,92 (1H, m, H-2'), 5,03 (1H, m, H-4'), 4,32 (2H, m, H-5'), 3,97 (2H, m, ala-NH, ala-CH), 3,71 (1,5H, s, OMe, B), 3,70 (1,5H, s, OMe, A), 1,86 (1,5H, s, 5-CH_{3}, B), 1,80 (1,5H, d, 5-CH_{3}, A), 1,36 (3H, m, ala-CH_{3}).H 1 (CDCl 3): 9.06 (1H, s, NH), 7.45 (5H, m, H-6, Ph), 7.03 (1H, m, H-1 '), 6.31 (1H, m, H-3 '), 5.92 (1H, m, H-2 '), 5.03 (1H, m, H-4'), 4.32 (2H, m, H-5 '), 3.97 (2H, m, NH-wing, CH-wing), 3.71 (1.5H, s, OMe, B), 3.70 (1.5H, s, OMe, A), 1.86 (1.5H, s, 5-CH3, B), 1.80 (1.5H, d, 5-CH 3, A), 1.36 (3H, m, ala-CH 3).
C^{13} (CDCl_{3}): 174,06 (d, ala-CO, A, J=6,8 Hz), 173,89 (d, ala-CO, B, 5=6,8 Hz), 163,91 (C-4, A), 163,86 (C-4, B), 150,96 (C-2), 150,71 (d, a-Ph, J=5,9 Hz), 135,86 (C-6, A), 135,66 (C-6, B), 133,30 (C-3', A), 133,02 (C-3', B), 132,00 (c, c-Ph, J=32,0 Hz), 130,66 (e-Ph), 127,84 (C-2', B), 127,74 (C-2', A), 123,98 (f-Ph, A), 123,84 (g, CF_{3}, J=272,0 Hz), 123,79 (f-Ph, B), 122,14 (d-Ph), 117,54 (d, b-Ph, J=3,9 Hz), 111,61 (C-5, B), 111,44 (C-5, A), 90,04 (C-1', B), 89,77 (C-1', A), 84,61 (d, C-4', J=7,8 Hz), 67,60 (d, C-5', B, J=4,9 Hz), 66,89 (d, C-5', A, J=4,9 Hz), 52,87 (OMe), 50,32 (d, ala-CH, A, J=4,8 Hz), 50,26 (d, ala-CH, B, J=4,8 Hz), 21,11 (d, ala-CH_{3}, B, J=4,9 Hz), 20,99 (d, ala-CH_{3}, A, J=4,9 Hz), 12,55 (5-CH_{3}, B), 12,47 (5-CH_{3}, A).C 13 (CDCl 3): 174.06 (d, ala-CO, A, J = 6.8 Hz), 173.89 (d, wing-CO, B, 5 = 6.8 Hz), 163.91 (C-4, A), 163.86 (C-4, B), 150.96 (C-2), 150.71 (d, a-Ph, J = 5.9 Hz), 135.86 (C-6, A), 135.66 (C-6, B), 133.30 (C-3 ', A), 133.02 (C-3', B), 132.00 (c, c-Ph, J = 32.0 Hz), 130.66 (e-Ph), 127.84 (C-2 ', B), 127.74 (C-2 ', A), 123.98 (f-Ph, A), 123.84 (g, CF 3, J = 272.0 Hz), 123.79 (f-Ph, B), 122.14 (d-Ph), 117.54 (d, b-Ph, J = 3.9 Hz), 111.61 (C-5, B), 111.44 (C-5, A), 90.04 (C-1 ', B), 89.77 (C-1', A), 84.61 (d, C-4 ', J = 7.8 Hz), 67.60 (d, C-5 ', B, J = 4.9 Hz), 66.89 (d, C-5', A, J = 4.9 Hz), 52.87 (OMe), 50.32 (d, wing-CH, A, J = 4.8 Hz), 50.26 (d, ala-CH, B, J = 4.8 Hz), 21.11 (d, ala-CH 3, B, J = 4.9 Hz), 20.99 (d, ala-CH 3, A, J = 4.9 Hz), 12.55 (5-CH 3, B), 12.47 (5-CH 3, TO).
MS: C_{21}H_{24}N_{3}O_{8}PF_{3}: 534 (MH^{+}, 6), 408 (MH^{+}-timina, 8), 268 (10), 149 (10), 81 (C_{5}H_{5}O, pico base). Masa exacta: esperada 534,1253; encontrada 534,1201MS: C 21 H 24 N 3 O 8 PF 3: 534 (MH <+>, 6), 408 (MH <+> - thymine, 8), 268 (10), 149 (10), 81 (C 5 H 5 O, base peak). Exact mass: expected 534,1253; found 534.1201
HPLC: RT = 30,56 minHPLC: RT = 30.56 min
Rendimiento = 70%Yield = 70%
P^{31} (CDCl_{3}) 2,83 y 3,42 ppmP 31 (CDCl 3) 2.83 and 3.42 ppm
(CDCl_{3}): 9,74 (1H, s, NH), 7,40 (1H, s, H-6), 7,29 (3H, m, Ph), 7,14 (1H, m, H-1'), 6,44 (1H, m, H-3'), 6,04 (1H, m, H-2'), 5,14 (1H, m, H-4'), 4,48-4,07 (5H, m, ala-NH, ala-CH, H-5'), 3,84 (3H, s, OMe), 1,97 (1,5H, s, 5-CH_{3}, A), 1,92 (1,5H, s, 5-CH_{3}, B), 1,48 (3H, m, ala-CH_{3}).(CDCl3): 9.74 (1H, s, NH), 7.40 (1H, s, H-6), 7.29 (3H, m, Ph), 7.14 (1H, m, H-1 '), 6.44 (1H, m, H-3'), 6.04 (1H, m, H-2 '), 5.14 (1H, m, H-4'), 4.48-4.07 (5H, m, wing-NH, CH-wing, H-5 '), 3.84 (3H, s, OMe), 1.97 (1.5H, s, 5-CH3, A), 1.92 (1.5H, s, 5-CH 3, B), 1.48 (3H, m, ala-CH 3).
C^{13} (CDCl_{3}) 173,93 (ala-CO), 164,09 (C-4), 151,27 (i-Ph), 151,06 (C-2), 136,01 (m-Ph), 135,60 (C-6), 133,14 (C-3', B), 132,89 (C-3', A), 127,83 (C-2'), 125,69 (p-Ph), 119,40 (o-Ph), 111,54 (C-5, A), 111,40 (C-5, B), 90,03 (C-1', A), 89,74 (C-1', B), 84,60 (C-4'), 67,68 (C-5', A), 66,98 (C-5', B), 52,85 (OMe), 50,26 (ala-CH), 20,93 (ala-CH_{3}), 12,51 (5-CH_{3}).C 13 (CDCl 3) 173.93 (wing-CO), 164.09 (C-4), 151.27 (i-Ph), 151.06 (C-2), 136.01 (m-Ph), 135.60 (C-6), 133.14 (C-3 ', B), 132.89 (C-3', A), 127.83 (C-2 '), 125.69 (p-Ph), 119.40 (o-Ph), 111.54 (C-5, A), 111.40 (C-5, B), 90.03 (C-1 ', A), 89.74 (C-1 ', B), 84.60 (C-4'), 67.68 (C-5 ', A), 66.98 (C-5', B), 52.85 (OMe), 50.26 (ala-CH), 20.93 (wing-CH 3), 12.51 (5-CH 3).
MS: C_{20}H_{23}N_{3}O_{8}PCl_{2}: 534 (MH^{+}, 8), 408 (MH^{+}-timina, 12), 391 (10), 149 (12), 127 (timinaH^{+}, 12), 81 (C_{5}H_{5}O, pico base).MS: C 20 H 23 N 3 O 8 PCl 2: 534 (MH +, 8), 408 (MH + - thymine, 12), 391 (10), 149 (12), 127 (thymineH +, 12), 81 (C5H5O, peak base).
Masa exacta: esperada 534,0600; encontrada 534,0589Exact mass: expected 534.0600; found 534,0589
HPLC: RT = 32,19 minHPLC: RT = 32.19 min
Rendimiento = 92%Yield = 92%
P^{31} (CDCl_{3}) 3,40 y 4,04 ppmP 31 (CDCl 3) 3.40 and 4.04 ppm
H^{1} (CDCl_{3}) 1,24 y 1,26 (d, 3H, J=6,8Hz, CH_{3} ala); 1,70 y 1,74 (s, 3H, 5CH_{3}); 3,86-4,28 (m, 4H, H5'+CH ala+NH); 4,85 (m, 1H, H4'); 5,04 y 5,06 (s, 2H, CH_{2}Ph); 5,74 (d, 1H, H2'); 6,16 (dd, 1H, H3'); 6,90 (m, 1H, H1'); 7,00-7,30 (m, 11H, Ar + H6); 9,61 (d, 1H, NH)H 1 (CDCl 3) 1.24 and 1.26 (d, 3H, J = 6.8Hz, CH 3 wing); 1.70 and 1.74 (s, 3H, 5CH3); 3.86-4.28 (m, 4H, H5 '+ CH wing + NH); 4.85 (m, 1H, H4 '); 5.04 and 5.06 (s, 2H, CH2 Ph); 5.74 (d, 1H, H2 '); 6.16 (dd, 1H, H3 '); 6.90 (m, 1H, H1 '); 7.00-7.30 (m, 11H, Ar + H6); 9.61 (d, 1H, NH)
C^{13} (CDCl_{3}): 12,52 (5CH_{3}); 20,98 (CH_{3} ala); 50,36-50,52 (CH ala); 66,70-67,18 (C5'); 67,46 (CH_{2}Ph); 84,63-84,76-84,88 (C4'); 89,68-89,88 (C1'); 111,44-111,55 (C5); 120,18-120,25-120,36-120,43 (Ar orto, OPh); 125,31 (Ar para, OPh); 127,48-127,61 (C2'); 128,45-128,79-128,83 (Ar, CH_{2}Ph); 129,87-129,93 (Ar meta, OPh); 133,16-133,45 (C3'); 135,35 (Ar1, CH_{2}Ph); 135,79-136,07 (C6); 150,44 (Ar1, OPh); 151,18 (C2); 164,21-164,28 (C4); 173,42-173,51-173,65 (CO ala)C 13 (CDCl 3): 12.52 (5CH 3); 20.98 (CH 3 wing); 50.36-50.52 (CH wing); 66.70-67.18 (C5 '); 67.46 (CH2 Ph); 84.63-84.76-84.88 (C4 '); 89.68-89.88 (C1 '); 111.44-111.55 (C5); 120,18-120,25-120,36-120.43 (Ar ortho, OPh); 125.31 (Ar para, OPh); 127.48-127.61 (C2 '); 128.45-128.79-128.83 (Ar, CH2 Ph); 129.87-129.93 (Ar meta, OPh); 133.16-133.45 (C3 '); 135.35 (Ar1, CH2 Ph); 135.79-136.07 (C6); 150.44 (Ar1, OPh); 151.18 (C2); 164.21-164.28 (C4); 173.42-173.51-173.65 (CO wing)
HPLC: RT = 34,96 y 35,07 minHPLC: RT = 34.96 and 35.07 min
MS: C_{26}H_{28}O_{8}N_{3}P: 542(MH^{+8}; 17); 416 (MH^{+o}base; 40); 81(100).MS: C 26 H 28 O 8 N 3 P: 542 (MH + 8; 17); 416 (MH + or base; 40); 81 (100).
Masa exacta: esperada 542,1716; encontrada 542,1712Exact mass: expected 542.1716; found 542.1712
Rendimiento = 88%Yield = 88%
P^{31} (CDCl_{3}): 3,07 y 3,62 ppmP 31 (CDCl 3): 3.07 and 3.62 ppm
H^{1} (CDCl_{3}) 1,26 y 1,28 (d, 3H, J=6,8Hz, CH_{3} ala); 1,75 y 1,80 (s, 3H, 5CH_{3}); 2,11 (s, 1H, NH); 3,64 (s, 3H, OMe); 3,92-4,30 (m, 3H, H5'+CHala); 4,98 (m, 1H, H4'); 5,87 (m, 1H, H2'); 6,26 (m, 1H, H3'); 6,96 (m, 1H, H1'); 7,30-7,60 (m, 4H, Ar + H6); 9,41 (s ancho, 1H, NH)H 1 (CDCl 3) 1.26 and 1.28 (d, 3H, J = 6.8Hz, CH 3 wing); 1.75 and 1.80 (s, 3H, 5CH3); 2.11 (s, 1 H, NH); 3.64 (s, 3H, OMe); 3.92-4.30 (m, 3H, H5 '+ CHala); 4.98 (m, 1H, H4 '); 5.87 (m, 1H, H2 '); 6.26 (m, 1H, H3 '); 6.96 (m, 1H, H1 '); 7.30-7.60 (m, 4H, Ar + H6); 9.41 (s wide, 1H, NH)
C^{13} (CDCl_{3}): 12,51 (5CH_{3}); 21,00 (CH_{3} ala); 50,24 CHala); 52,80 (OMe); 67,37-67,83 (C5'); 84,49-84,61 (C4'); 89,80-89,92 (C1'); 111,60 (C5); 115,49 (Ar2); 118,26 (Ar4); 122,61-122,89 (Ar6); 127,70 (C2'); 131,86 (Ar5); 133,06-133,21 (C3'); 135,64 (Ar3); 135,75-135,88 (C6); 147,01 (Ar1); 151,07 (C2); 164,03 (C4); 173,71-173,82 (COala)C 13 (CDCl 3): 12.51 (5CH 3); 21.00 (CH 3 wing); 50.24 CHala); 52.80 (OMe); 67.37-67.83 (C5 '); 84.49-84.61 (C4 '); 89.80-89.92 (C1 '); 111.60 (C5); 115.49 (Ar2); 118.26 (Ar4); 122.61-122.89 (Ar6); 127.70 (C2 '); 131.86 (Ar5); 133.06-133.21 (C3 '); 135.64 (Ar3); 135.75-135.88 (C6); 147.01 (Ar1); 151.07 (C2); 164.03 (C4); 173.71-173.82 (COala)
HPLC: RT = 41,17 y 41,30 minHPLC: RT = 41.17 and 41.30 min
MS: C_{20}H_{22}O_{8}N_{3}PBr_{2}: 622,624,626 (MH^{+0}; 3,6,3); 496,498,500MS: C 20 H 22 O 8 N 3 PBr 2: 622,624,626 (MH + 0; 3,6,3); 496,498,500
(MH^{+o} base; 5,9,5); 81 (100). Masa exacta: esperada 621,9516; encontrada 621,9507(MH + or base; 5,9.5); 81 (100). Exact mass: expected 621.9516; Found 621.9507
Rendimiento = 76%Yield = 76%
P^{31} (CDCl_{3}) 4,74 y 5,66 ppmP 31 (CDCl 3) 4.74 and 5.66 ppm
H^{1} (CDCl_{3}) 1,34 y 1,36 (d, 3H, J=6,7Hz, CH_{3} ala); 1,75 y 1,81 (s, 3H, 5CH_{3}); 3,69 (s, 3H, OMe); 3,92-4,40 (m, 4H, H5'+CH ala+NH); 4,97 (m, 1H, H4'); 5,85 (m, 1H, H2'); 6,29 (m, 1H, H3'); 6,93 (m, 1H, H1'); 7,19 (m, 1H, H6); 9,38 (s ancho, 1H, NH)H 1 (CDCl 3) 1.34 and 1.36 (d, 3H, J = 6.7Hz, CH 3 wing); 1.75 and 1.81 (s, 3H, 5CH3); 3.69 (s, 3H, OMe); 3.92-4.40 (m, 4H, H5 '+ CH wing + NH); 4.97 (m, 1H, H4 '); 5.85 (m, 1H, H2 '); 6.29 (m, 1H, H3 '); 6.93 (m, 1H, H1 '); 7.19 (m, 1H, H6); 9.38 (wide s, 1H, NH)
C^{13} (CDCl_{3}) 12,23-12,43 (5CH_{3}); 20,83 (CH_{3} ala); 50,22-50,34 (CH ala); 52,99 (OMe); 67,75-68,37 (C5'); 84,42-84,52 (C4'); 89,87-90,17 (Cl'); 111,75 (C5); 127,69-127,93 (C2'); 132,86-133,13 (C3'); 132-143 (m, Ar); 135,74-135,96 (C6); 151,11 (C2); 164,15 (C4); 173,64-173,76 (COala)C 13 (CDCl 3) 12.23-12.43 (5CH3); 20.83 (CH 3 wing); 50.22-50.34 (CH to); 52.99 (OMe); 67.75-68.37 (C5 '); 84.42-84.52 (C4 '); 89.87-90.17 (Cl '); 111.75 (C5); 127.69-127.93 (C2 '); 132.86-133.13 (C3 '); 132-143 (m, Ar); 135.74-135.96 (C6); 151.11 (C2); 164.15 (C4); 173.64-173.76 (COala)
Masa (matriz NOBA): C_{20}H_{19}O_{8}N_{3}PF_{5}: 556 (MH^{+o},31); 578 (M^{o+}Na, 100)Mass (NOBA matrix): C 20 H 19 O 8 N 3 PF 5: 556 (MH + o, 31); 578 (M o + Na, 100)
HPLC: RT = 35,90 minHPLC: RT = 35.90 min
Rendimiento = 88%Yield = 88%
P^{31} (CDCl_{3}) 3,99 y 4,60 ppmP 31 (CDCl 3) 3.99 and 4.60 ppm
H^{1} (CDCl_{3}): 0,94 (m, 3H, CH_{3}CH_{2}); 1,28-1,41 (m, 9H, CH_{3} ala + 3XCH_{2}); 1,65 (m, 2H, CO_{2}CH_{2}CH_{2}); 1,90 y 1,93 (s, 3H, 5CH_{3}); 4,00-4,20 (m, 4H, CH ala + NH ala + CO_{2}CH_{2}); 4,37 (m, 2H, H5'); 5,05 (m, 1H, H4'); 5,94 (m, 1H, H2'); 6,38 (m, 1H, H3'); 7,10 (m, 1H, H1'); 7,15-7,36 (m, 6H, Ar + H6); 9,48 y 9,51 (s, 1H, NH)H 1 (CDCl 3): 0.94 (m, 3H, C H 3 CH 2); 1.28-1.41 (m, 9H, CH 3 wing + 3XCH 2); 1.65 (m, 2H, CO 2 CH 2 C H 2); 1.90 and 1.93 (s, 3H, 5CH3); 4.00-4.20 (m, 4H, CH wing + NH wing + CO 2 CH 2); 4.37 (m, 2H, H5 '); 5.05 (m, 1H, H4 '); 5.94 (m, 1H, H2 '); 6.38 (m, 1H, H3 '); 7.10 (m, 1H, H1 '); 7.15-7.36 (m, 6H, Ar + H6); 9.48 and 9.51 (s, 1H, NH)
C^{13} (CDCl_{3}) 12,76 (5CH_{3}); 14,39 (CH_{3}CH_{2}); 21,45 (CH_{3} ala); 22,88, 25,82, 28,82 y 31,72 (CH_{2}); 50,63 (CH ala); 66,26 (OCH_{2}); 66,89-67,43 (C5'); 85,03 (C4'); 89,97 (Cl'); 111,68-111,83 (C5); 120,55 (Ar orto); 125,57 (Ar para); 127,86 (C2'); 130,15 (Ar meta); 133,47-133,70 (C3'); 136,03-136,31 (C6); 150,72 (Ar ipso); 151,37-151,39 (C2); 164,35-164,42 (C4); 174,02 (CO ala)C 13 (CDCl 3) 12.76 (5CH 3); 14.39 (C H 3 CH 2); 21.45 (CH 3 wing); 22.88, 25.82, 28.82 and 31.72 (CH2); 50.63 (CH wing); 66.26 (OCH2); 66.89-67.43 (C5 '); 85.03 (C4 '); 89.97 (Cl '); 111.68-111.83 (C5); 120.55 (Ar ortho); 125.57 (Ar para); 127.86 (C2 '); 130.15 (Ar meta); 133.47-133.70 (C3 '); 136.03-136.31 (C6); 150.72 (Ar ipso); 151.37-151.39 (C2); 164.35-164.42 (C4); 174.02 (CO wing)
Masa (Matriz NOBA): C_{25}H_{34}O_{8}N_{3}P: 536 (MH^{+o}, 24); 558 (M^{o+}Na, 37)Mass (NOBA Matrix): C 25 H 34 O 8 N 3 P: 536 (MH + o, 24); 558 (M o + Na, 37)
Rendimiento = 89%Yield = 89%
P^{31} (CDCl_{3}): 3,96 y 4,35 ppmP 31 (CDCl 3): 3.96 and 4.35 ppm
H^{1} (CDCl_{3}): 1,89 (s, 3H, 5CH_{2}); 3,00 (m, 2H, CH_{2}Ph); 3,74 (s, 3H, OMe); 3,80-4,28 (m, 4H, CH ala + NH ala + H5'); 4,94 (m, 1H, H4'); 5,91 (m, 1H, H2'); 6,21-6,30 (m, 1H, H3'); 7,04-7,32 (m, 12H, Ar + H1' + H6); 9,35 (s, 1H, NH)H 1 (CDCl 3): 1.89 (s, 3H, 5CH 2); 3.00 (m, 2H, CH2 Ph); 3.74 (s, 3H, OMe); 3.80-4.28 (m, 4H, CH wing + NH wing + H5 '); 4.94 (m, 1H, H4 '); 5.91 (m, 1H, H2 '); 6.21-6.30 (m, 1H, H3 '); 7.04-7.32 (m, 12H, Ar + H1 '+ H6); 9.35 (s, 1 H, NH)
C^{13} (CDCl_{3}): 12,54 (5CH_{3}); 40,55 (CH_{2}Ph); 52,63 (OMe); 55,72-56,01 (CH ala); 66,50-67,10 (C5'); 84,78 (C4'); 89,71-89,95 (Cl'); 111,53-111,64 (C5); 120,28 (Ar orto, OPh); 125,40 (Ar para, OPh); 127,52 (C2'); 128,86, 129,65 y 129,98 (Ar, CH_{2}Ph); 129,86-129,92 (Ar meta, OPh); 133,18-133,50 (C3'); 135,72 (Ar ipso, CH_{2}Ph); 135,79-136,06 (C6); 150,46 (Ar ipso, OPh); 151,13-151,17 (C2); 164,12-164,18 (C4); 173,00 (Co ala)C 13 (CDCl 3): 12.54 (5CH 3); 40.55 (CH2 Ph); 52.63 (OMe); 55.72-56.01 (CH wing); 66.50-67.10 (C5 '); 84.78 (C4 '); 89.71-89.95 (Cl '); 111.53-111.64 (C5); 120.28 (Ar ortho, OPh); 125.40 (Ar para, OPh); 127.52 (C2 '); 128.86, 129.65 and 129.98 (Ar, CH2 Ph); 129.86-129.92 (Ar meta, OPh); 133.18-133.50 (C3 '); 135.72 (Ar ipso, CH2 Ph); 135.79-136.06 (C6); 150.46 (Ar ipso, OPh); 151.13-151.17 (C2); 164.12-164.18 (C4); 173.00 (Co wing)
Masa (matriz NOBA): C_{20}6H_{28}O_{8}N_{3}P: 542 (MH^{+o},77); 564 (M^{o+}Na, 29)Mass (NOBA matrix): C 20 6H 28 O 8 N 3 P: 542 (MH + o, 77); 564 (M o + Na, 29)
Rendimiento = 87%Yield = 87%
P^{31} (CDCl_{3}) 4,18 y 4,83 ppmP 31 (CDCl 3) 4.18 and 4.83 ppm
H^{1} (CDCl_{3}) 0,91 (m, 6H, (CH_{3})_{2}CH); 1,42-1,70 (m, 3H, CH_{2}CH(CH_{3})_{2}); 1,91 y 1,93 (s, 3H, 5CH_{3}); 3,73 (s, 3H, OMe); 3,76-3,98 (m, 2H, CH ala + NH ala); 4,28-4,46 (m, 2H, H5'); 5,08 (m, 1H, H4'); 5,96 (m, 1H, H2'); 6,36 (m, 1H, H3'); 7,09 (m, 1H, H1'); 7,18-7,35 (m, 6H, Ar + H6); 9,35 (s, 1H, NH)H 1 (CDCl 3) 0.91 (m, 6H, (CH 3) 2 CH); 1.42-1.70 (m, 3H, C H 2 CH (CH 3) 2); 1.91 and 1.93 (s, 3H, 5CH3); 3.73 (s, 3H, OMe); 3.76-3.98 (m, 2H, CH wing + NH wing); 4.28-4.46 (m, 2H, H5 '); 5.08 (m, 1H, H4 '); 5.96 (m, 1H, H2 '); 6.36 (m, 1H, H3 '); 7.09 (m, 1H, H1 '); 7.18-7.35 (m, 6H, Ar + H6); 9.35 (s, 1 H, NH)
C^{13} (CDCl_{3}): 12,76 (5CH_{3}); 22,23-23,01 ((CH_{3})_{2}CH); 24,75 (CH(CH_{3})_{2}); 43,86-44,11 (CH_{2}CH(CH_{3})_{2}); 52,75 (OMe); 53,42-53,60 (CH ala); 66,92-67,55 (C5'); 85,62 (C4'); 89,92-90,19 (Cl'); 111,69-111,83 (C5); 120,37-120,62 (Ar orto); 125,55-125,58 (Ar para); 127,79 (C2'); 130,12 (Ar meta); 133,51-133,70 (C3'); 136,00-136,36 (C6); 151,05 (Ar ipso); 151,38 (C2); 164,39-164,50 (C4); 174,55-174,88 (CO ala)C 13 (CDCl 3): 12.76 (5CH 3); 22.23-23.01 ((CH 3) 2 CH); 24.75 (CH (CH 3) 2); 43.86-44.11 (CH 2 CH (CH 3) 2); 52.75 (OMe); 53.42-53.60 (CH wing); 66.92-67.55 (C5 '); 85.62 (C4 '); 89.92-90.19 (Cl '); 111.69-111.83 (C5); 120.37-120.62 (Ar ortho); 125.55-125.58 (Ar para); 127.79 (C2 '); 130.12 (Ar meta); 133.51-133.70 (C3 '); 136.00-136.36 (C6); 151.05 (Ar ipso); 151.38 (C2); 164.39-164.50 (C4); 174.55-174.88 (CO wing)
Masa (matriz NOBA): C_{23}H_{30}O_{8}N_{3}P: 508 (MH^{+o},62); 530 (M^{o+}Na, 59)Mass (NOBA matrix): C 23 H 30 O 8 N 3 P: 508 (MH + o, 62); 530 (M o + Na, 59)
Rendimiento = 86%Yield = 86%
P^{31} (CDCl_{3}): 4,85 y 5,40 ppmP 31 (CDCl 3): 4.85 and 5.40 ppm
H^{1} (CDCl_{3}): 0,92 (m, 6H, (CH_{3})_{2}CH); 1,82 (m, 3H, CH(CH_{3})_{2}); 1,89 y 1,91 (s, 3H, 5CH_{3}); 3,76 (s, 3H, OMe); 3,82 (m, 2H, CH ala + NH ala); 4,30-4,48 (m, 2H, H5'); 5,07 (m, 1H, H4'); 5,96 (m, 1H, H2'), 6,38 (m, 1H, H3'); 7,10 (m, 1H, H1'); 7,18-7,35 (m, 6H, Ar + H6); 9,31 (s, 1H, NH)H 1 (CDCl 3): 0.92 (m, 6H, (C H 3) 2 CH); 1.82 (m, 3H, CH (CH 3) 2); 1.89 and 1.91 (s, 3H, 5CH3); 3.76 (s, 3H, OMe); 3.82 (m, 2H, CH wing + NH wing); 4.30-4.48 (m, 2H, H5 '); 5.07 (m, 1H, H4 '); 5.96 (m, 1H, H2 '), 6.38 (m, 1H, H3'); 7.10 (m, 1H, H1 '); 7.18-7.35 (m, 6H, Ar + H6); 9.31 (s, 1H, NH)
C^{13} (CDCl_{3}): 12,80 (5CH_{3}); 17,77-19,24 ((CH_{3})_{2}CH); 32,43-32,62 (CH(CH_{3})_{2}); 52,67 (OMe); 60,32-60,38 (CH ala); 66,92-67,65 (C5'); 85,04 (C4'); 89,98-90,24 (Cl'); 111,76-111,87 (C5); 120,45-120,56 (Ar orto); 125,54-125,59 (Ar para); 127,81-127,86 (C2'); 130,13-130,17 (Ar meta); 133,51-133,72 (C3'); 136,01-136,28 (C6); 150,83 (Ar ipso); 150,87-151,34 (C2); 164,30-164,37 (C4); 173,56-173,65 (CO ala)C 13 (CDCl 3): 12.80 (5CH 3); 17.77-19.24 ((CH 3) 2 CH); 32.43-32.62 (CH (CH 3) 2); 52.67 (OMe); 60.32-60.38 (CH wing); 66.92-67.65 (C5 '); 85.04 (C4 '); 89.98-90.24 (Cl '); 111.76-111.87 (C5); 120.45-120.56 (Ar ortho); 125.54-125.59 (Ar para); 127.81-127.86 (C2 '); 130,13-130.17 (Ar meta); 133.51-133.72 (C3 '); 136.01-136.28 (C6); 150.83 (Ar ipso); 150.87-151.34 (C2); 164.30-164.37 (C4); 173.56-173.65 (CO wing)
Masa: C_{22}H_{28}O_{8}N_{3}P: 493,6 (MH^{+o}, 100)Mass: C 22 H 28 O 8 N 3 P: 493.6 (MH <+>, 100)
Rendimiento = 90%Yield = 90%
P^{31} (CDCl_{3}): 4,89 y 5,52 ppmP 31 (CDCl 3): 4.89 and 5.52 ppm
H^{1} (CDCl_{3}): 1,79 y 1,83 (s, 3H, 5CH_{3}); 3,69 (s, 3H, OMe); 3,70-4,05 (m, 4H, CH_{2}NH + CH ala + NH ala); 4,32 (m, 2H, HS'); 4,99 (m, 1H, H4'); 5,92 (m, 1H, H2'); 6,38 (m, 1H, H3'); 6,98 (m, 1H, H1'); 7,05-7,38 (m, 6H, Ar + H6); 9,44 y 9,46 (s, 1H, NH)H 1 (CDCl 3): 1.79 and 1.83 (s, 3H, 5CH3); 3.69 (s, 3H, OMe); 3.70-4.05 (m, 4H, CH 2 NH + CH wing + NH wing); 4.32 (m, 2H, HS '); 4.99 (m, 1H, H4 '); 5.92 (m, 1H, H2 '); 6.38 (m, 1H, H3 '); 6.98 (m, 1H, H1 '); 7.05-7.38 (m, 6H, Ar + H6); 9.44 and 9.46 (s, 1H, NH)
C^{13} (CDCl_{3}): 12,75 (5CH_{3}); 43,15 (CH_{2}NH); 52,94 (OMe); 66,78-67,52 (C5'); 84,98-85,10 (C4'); 89,68-90,16 (C1'); 111,69-111,80 (C5); 120,46-120,59 (Ar orto); 125,66 (Ar para); 127,66-127,91 (C2'); 130,22 (Ar meta); 133,48-133,87 (C3'); 136,11-136,40 (C6); 150,65 (Ar ipso); 151,45 (C2); 164,46 (C4); 171,41-171,51 (CO ala)C 13 (CDCl 3): 12.75 (5CH 3); 43.15 ( C H2 NH); 52.94 (OMe); 66.78-67.52 (C5 '); 84.98-85.10 (C4 '); 89.68-90.16 (C1 '); 111.69-111.80 (C5); 120.46-120.59 (Ar ortho); 125.66 (Ar para); 127.66-127.91 (C2 '); 130.22 (Ar meta); 133.48-133.87 (C3 '); 136.11-136.40 (C6); 150.65 (Ar ipso); 151.45 (C2); 164.46 (C4); 171.41-171.51 (CO wing)
Masa (matriz NOBA): C_{19}H_{22}O_{8}N_{3}P: 452 (MH^{+o},74); 474 (M^{o+}Na, 46)Mass (NOBA matrix): C 19 H 22 O 8 N 3 P: 452 (MH + o, 74); 474 (M o + Na, 46)
Rendimiento = 81%Yield = 81%
P^{31} (CDCl_{3}): 4,09 y 4,86 ppmP 31 (CDCl 3): 4.09 and 4.86 ppm
H^{1} (CDCl_{3}): 1,74 y 1,79 (s, 3H, CH_{3}S); 1,94 y 1,97 (s, 3H, 5CH_{3}); 1,80-2,40 (m, 5H, CHCH_{2}CH_{2}S); 3,72 y 3,74 (s, 3H, OMe); 3,98-4,32 (m, 4H, H5' + CH ala + NH ala); 4,96 (m, 1H, H4'); 5,84 (m, 1H, H2'); 6,26 (m, 1H, H3'); 6,96 (m, 1H, 1H'); 7,05-7,25 (m, 6H, Ar + H6); 9,58 (s ancho, 1H, NH)H 1 (CDCl 3): 1.74 and 1.79 (s, 3H, CH 3 S); 1.94 and 1.97 (s, 3H, 5CH3); 1.80-2.40 (m, 5H, C H C H 2 C H 2 S); 3.72 and 3.74 (s, 3H, OMe); 3.98-4.32 (m, 4H, H5 '+ CH wing + NH wing); 4.96 (m, 1H, H4 '); 5.84 (m, 1H, H2 '); 6.26 (m, 1H, H3 '); 6.96 (m, 1H, 1H '); 7.05-7.25 (m, 6H, Ar + H6); 9.58 (wide s, 1H, NH)
C^{13} (CDCl_{3}): 12,80 (5CH_{3}); 15,68 (CH_{3}S); 29,95 (CH_{2}SCH_{3}); 33,73-33,85 (CH_{2}CH_{2}S); 53,06 (OMe); 53,81-54,07 (NHCH); 67,05-67,70 (C5'); 84,90-85,03 (C4'); 89,98-90,23 (Cl'); 111,66-111,86 (C5); 120,39-120,66 (Ar orto); 125,63 (Ar para); 127,81-127,91 (C2'); 130,18 (Ar Meta); 133,44-133,69 (C3'); 136,00-136,38 (C6); 150,72-150,80 (Ar ipso); 151,41 (C2); 164,52 (C4); 173,61-173,94 (CO ala)C 13 (CDCl 3): 12.80 (5CH 3); 15.68 (CH 3 S); 29.95 (C H 2 SCH 3); 33.73-33.85 ( C H 2 CH 2 S); 53.06 (OMe); 53.81-54.07 (NH C H); 67.05-67.70 (C5 '); 84.90-85.03 (C4 '); 89.98-90.23 (Cl '); 111.66-111.86 (C5); 120.39-120.66 (Ar ortho); 125.63 (Ar para); 127.81-127.91 (C2 '); 130.18 (Ar Meta); 133.44-133.69 (C3 '); 136.00-136.38 (C6); 150.72-150.80 (Ar ipso); 151.41 (C2); 164.52 (C4); 173.61-173.94 (CO wing)
Masa (matriz NOBA): C_{22}H_{28}O_{8}N_{3}PS: 526 (MH^{+o}, 46); 548 (Mº^{+},6Na, 21)Mass (NOBA matrix): C 22 H 28 O 8 N 3 PS: 526 (MH + o, 46); 548 (Mº +, 6Na, 21)
Rendimiento = 82%Yield = 82%
P^{31} (CDCl_{3}): 3,68 y 4,18 ppmP 31 (CDCl 3): 3.68 and 4.18 ppm
H^{1} (CDCl_{3}): 1,40 y 1,42 (d, 3H, J=6,7Hz, CH_{3} ala); 1,90 y 1,92 (s, 3H, 5CH_{3}); 4,04-4,40 (m, 4H, H5'+CHala + NH ala); 4,98 (m, 1H, H4'); 5,20 (s, 2H, CH_{2}Ph); 5,91 (m, 1H, H2'); 6,27 y 6,35 (m, 1H, H3'); 7,06 (s ancho, 1H, H1'); 7,30-7,70 (m, 9H, Ar + H6); 9,52 (s, 1H, NH)H 1 (CDCl 3): 1.40 and 1.42 (d, 3H, J = 6.7Hz, CH 3 wing); 1.90 and 1.92 (s, 3H, 5CH3); 4.04-4.40 (m, 4H, H5 '+ CHala + NH wing); 4.98 (m, 1 H, H4 '); 5.20 (s, 2H, CH2 Ph); 5.91 (m, 1H, H2 '); 6.27 and 6.35 (m, 1H, H3 '); 7.06 (broad s, 1H, H1 '); 7.30-7.70 (m, 9H, Ar + H6); 9.52 (s, 1 H, NH)
C^{13} (CDCl_{3}): 12,86 (5CH_{3}); 21,35 (CH_{3} ala); 50,68-50,76 (CHala); 67,67-68,03 (C5'); 67,88 (CH_{2}Ph); 84,85 (C4'); 90,10-90,20 (C1'); 111,88-111,92 (C5); 115,76-115,91 (Ar2); 118,62-118,72 (Ar4); 122,91-123,22 (Ar6); 127,98 (C2'); 128,75-129,01-129,12 (Ar o,m,p, CH_{2}Ph); 132,20 (Ar5); 133,38-133,51 (C3'); 135,48 (Ar ipso, CH_{2}Ph); 135,96 (Ar3); 136,21 (C6); 147,28 (Ar1); 151,39 (C2); 164,34-164,38 (C4); 173,47-173,62 (COala)C 13 (CDCl 3): 12.86 (5CH 3); 21.35 (CH 3 wing); 50.68-50.76 (CHala); 67.67-68.03 (C5 '); 67.88 (CH2 Ph); 84.85 (C4 '); 90.10-90.20 (C1 '); 111.88-111.92 (C5); 115.76-115.91 (Ar2); 118.62-118.72 (Ar4); 122.91-123.22 (Ar6); 127.98 (C2 '); 128.75-129.01-129.12 (Ar o, m, p, CH2 Ph); 132.20 (Ar5); 133.38-133.51 (C3 '); 135.48 (Ar ipso, CH2 Ph); 135.96 (Ar3); 136.21 (C6); 147.28 (Ar1); 151.39 (C2); 164.34-164.38 (C4); 173.47-173.62 (COala)
Masa (matriz NOBA) C_{26}H_{26}O_{8}N_{3}PBr:699-700-701 (MH^{+}º, 27-49-29); 721-722-723 (Mº^{+}Na, 17-21-17)Mass (NOBA matrix) C_26 H_ {26} O8 {3} PBr: 699-700-701 (MH + º, 27-49-29); 721-722-723 (M + Na, 17-21-17)
Rendimiento = 83%Yield = 83%
P^{31} (CDCl_{3}): 3,91 y 4,33 ppmP 31 (CDCl 3): 3.91 and 4.33 ppm
H^{1} (CDCl_{3}): 1,83 y 1,85 (s, 3H, 5CH_{3}); 3,01 (m, 2H, CHCH_{2}Ph); 3,78-4,30 (m, 4H, H5' + HNCH); 4,92 (m, 1H, H4'); 5,89 (m, 1H, H2'); 6,18 y 6,27 (m, 1H, H3'); 7,00-7,40 (m, 17H, Ar + H1' + H6); 9,35 (s ancho, 1H, NH)H 1 (CDCl 3): 1.83 and 1.85 (s, 3H, 5CH 3); 3.01 (m, 2H, CHC H2 Ph); 3.78-4.30 (m, 4H, H5 '+ H NC H ); 4.92 (m, 1H, H4 '); 5.89 (m, 1H, H2 '); 6.18 and 6.27 (m, 1H, H3 '); 7.00-7.40 (m, 17H, Ar + H1 '+ H6); 9.35 (wide s, 1H, NH)
C^{13} (CDCl_{3}): 12,62-12,75 (5CH_{3}); 40,65-40,73 (CHCH_{2}Ph); 55,95-56,26 (NHCH); 66,79 -67,27 (C5'); 67,80 (CH_{2}Ph); 84,87-85,05 (C4'); 89,92-90,14 (Cl'); 111,72-111,82 (C5); 120,45-120,52 (Ar orto, OPh); 125,60 (Ar para, OPh); 127,73 (C2'); 129,01-129,07-129,11-129,91- 130,15-130,38-135,29-135,85 (Ar, 2xCH_{2}Ph); 130,21 (Ar meta, OPh); 133,36-133,63 (C3'); 136,24 (C6); 150,68-150,77 (Ar ipso, OPh); 151,31-151,35 (C2); 164,28-164,34 (C4); 172,48-172,64 (Co ala)C 13 (CDCl 3): 12.62-12.75 (5CH 3); 40.65-40.73 (CH C H2 Ph); 55.95-56.26 (NHC H ); 66.79-67.27 (C5 '); 67.80 ( C H2 Ph); 84.87-85.05 (C4 '); 89.92-90.14 (Cl '); 111.72-111.82 (C5); 120.45-120.52 (Ar ortho, OPh); 125.60 (Ar para, OPh); 127.73 (C2 '); 129.01-129.07-129.11-129.91-130.15-130.38-135.29-135.85 (Ar, 2xCH2 Ph); 130.21 (Ar meta, OPh); 133.36-133.63 (C3 '); 136.24 (C6); 150.68-150.77 (Ar ipso, OPh); 151.31-151.35 (C2); 164.28-164.34 (C4); 172.48-172.64 (Co ala)
Masa (matriz NOBA): C_{32}H_{32}O_{8}N_{3}P: 618 (MH^{+}º, 78); 640 (Mº^{+},Na, 52)Mass (NOBA matrix): C 32 H 32 O 8 N 3 P: 618 (MH +, 78); 640 (M + +, Na, 52)
Rendimiento = 79%Yield = 79%
P^{31} (CDCl_{3}): 4,27 y 4,50 ppmP 31 (CDCl 3): 4.27 and 4.50 ppm
H^{1} (CDCl_{3}) 1,40 y 1,41 (s, 9H, tBu); 1,84 y 1,87 (s, 3H, 5CH_{3}); 3,00 (m, 2H, CH_{2}Ph); 3,76-4,28 (m, 4H, H5' + HNCH); 4,95 (m, 1H, H4'); 5,86 y 5,91 (m, 1H, H2'); 6,26 y 6,30 (m, 1H, H3'); 7,04 (m, 1H, H1'); 7,12-7,25 (m, 11H, Ar + H6); 9,38 y 9,40 (s ancho, 1H, NH)H 1 (CDCl 3) 1.40 and 1.41 (s, 9H, tBu); 1.84 and 1.87 (s, 3H, 5CH3); 3.00 (m, 2H, C H2 Ph); 3.76-4.28 (m, 4H, H5 '+ H NC H ); 4.95 (m, 1H, H4 '); 5.86 and 5.91 (m, 1H, H2 '); 6.26 and 6.30 (m, 1H, H3 '); 7.04 (m, 1H, H1 '); 7.12-7.25 (m, 11H, Ar + H6); 9.38 and 9.40 (wide s, 1H, NH)
C^{13} (CDCl_{3}): 12,76-12,79 (5CH_{3}); 28,31 ((CH_{3})_{3}C); 40,96-41,04 (CH_{2}Ph); 56,31-56,65 (NHCH); 66,79-67,28 (C5'); 82,90-82,92 ((CH_{3})_{3}C); 84,94-85,03 (C4'); 89,93-90,11 (C1'); 111,67-111,86 (C5); 120,45 (Ar orto, OPh); 125,52 (Ar para, OPh); 127,77 (C2'); 127,88-128,83-128,92-136,02 (Ar, CH_{2}Ph); 130,13 (Ar meta, OPh); 133,54-133,60 (C3'); 136,31 (C6); 150,75-150,84 (Ar ipso, OPh)); 151,36 (C2); 164,32-164,37 (C4); 171,89 (CO ala)C 13 (CDCl 3): 12.76-12.79 (5CH 3); 28.31 (( C H 3) 3 C); 40.96-41.04 ( C H2 Ph); 56.31-56.65 (NH C H); 66.79-67.28 (C5 '); 82.90-82.92 ((CH 3) 3 C ); 84.94-85.03 (C4 '); 89.93-90.11 (C1 '); 111.67-111.86 (C5); 120.45 (Ar ortho, OPh); 125.52 (Ar para, OPh); 127.77 (C2 '); 127.88-128.83-128.92-136.02 (Ar, CH2 Ph ); 130.13 (Ar meta, OPh); 133.54-133.60 (C3 '); 136.31 (C6); 150.75-150.84 (Ar ipso, OPh)); 151.36 (C2); 164.32-164.37 (C4); 171.89 (CO wing)
Masa (matriz NOBA): C_{29}H_{34}O_{8}N_{3}P: 584 (MH^{+}º, 26); 606 (Mº^{+}Na, 41)Mass (NOBA matrix): C 29 H 34 O 8 N 3 P: 584 (MH + º, 26); 606 (M + Na, 41)
Rendimiento = 83%Yield = 83%
P^{31} (CDCl_{3}): 4,11 y 4,71 ppmP 31 (CDCl 3): 4.11 and 4.71 ppm
H^{1} (CDCl_{3}): 1,08-1,82 (m, 16H, CH_{3} ala + 5CH_{3} + ciclohexilo); 3,79-4,14 (m, 2H, CH ala + NH ala); 4,27 (m, 2H, H5'); 4,69 (m, CH ciclohexilo); 4,96 (m, 1H, H4'); 5,80 (m, 1H, H2'); 6,24 (m, 1H, H3'); 6,98 (m, 1H, H1'); 7,04-7,32 (m, 6H, Ar + H6); 9,66 y 9,82 (s ancho, 1H, NH).H 1 (CDCl 3): 1.08-1.82 (m, 16H, CH 3 ala + 5CH 3 + cyclohexyl); 3.79-4.14 (m, 2H, CH wing + NH wing); 4.27 (m, 2H, H5 '); 4.69 (m, CH cyclohexyl); 4.96 (m, 1H, H4 '); 5.80 (m, 1 H, H2 '); 6.24 (m, 1H, H3 '); 6.98 (m, 1H, H1 '); 7.04-7.32 (m, 6H, Ar + H6); 9.66 and 9.82 (wide s, 1H, NH).
C^{13} (CDCl_{3}): 12,58 (5CH_{3}); 21,18-21,32 (CH_{3} ala); 23,73-25,40-31,49-31,58 (CH_{2} ciclohexilo); 50,47-50,61 (CH ala); 66,69-67,24 (C5'); 74,36 (CH ciclohexilo); 84,87 (C4'); 89,72-89,92 (C1'); 111,48-111,63 (C5); 120,26-120,49 (Ar orto); 125,32-125,37 (Ar para); 127,59-127,73 (C2'); 129,91-129,98 (Ar meta); 133,30-133,51 (C3'); 135,89-136,16 (C6); 150,53 (Ar ipso); 150,67-151,31 (C2); 164,36-164,41 (C4); 173,23 (CO ala).C 13 (CDCl 3): 12.58 (5CH 3); 21.18-21.32 (CH 3 wing); 23.73-25.40-31.49-31.58 (CH2cyclohexyl); 50.47-50.61 (CH wing); 66.69-67.24 (C5 '); 74.36 ( C H cyclohexyl); 84.87 (C4 '); 89.72-89.92 (C1 '); 111.48-111.63 (C5); 120.26-120.49 (Ar ortho); 125.32-125.37 (Ar para); 127.59-127.73 (C2 '); 129.91-129.98 (Ar meta); 133.30-133.51 (C3 '); 135.89-136.16 (C6); 150.53 (Ar ipso); 150.67-151.31 (C2); 164.36-164.41 (C4); 173.23 (CO wing).
Masa (matriz NOBA): C_{25}H_{32}O_{8}N_{3}P: 534 (MH^{+}º, 56); 556 (Mº^{+}Na, 42)Mass (NOBA matrix): C 25 H 32 O 8 N 3 P: 534 (MH +, 56); 556 (M + Na, 42)
Rendimiento = 79%Yield = 79%
P^{31} (CDCl_{3}): 4,17 y 4,67 ppm.P 31 (CDCl 3): 4.17 and 4.67 ppm.
H^{1} (CDCl_{3}): 1,34 (m, 3H, CH_{3} ala); 1,46 (m, 9H, CH_{3} tBu); 1,87 (d, 3H, 5CH_{3}); 3,82-4,06 (m, 2H, H5'); 4,29-4,49 (m, 2H, CH ala + NH ala); 5,05 (m, 1H, H4'); 5,91 (m, 1H, H2'); 6,35 (m, 1H, H3'); 7,06 (m, 1H, H1'); 7,15-7,40 (m, 6H, Ar +H6); 9,60 (s ancho, 1H, NH).H 1 (CDCl 3): 1.34 (m, 3H, CH 3 wing); 1.46 (m, 9H, CH 3 tBu); 1.87 (d, 3H, 5CH3); 3.82-4.06 (m, 2H, H5 '); 4.29-4.49 (m, 2H, CH wing + NH wing); 5.05 (m, 1H, H4 '); 5.91 (m, 1H, H2 '); 6.35 (m, 1H, H3 '); 7.06 (m, 1H, H1 '); 7.15-7.40 (m, 6H, Ar + H6); 9.60 (broad s, 1H, NH).
C^{13} (CDCl_{3}): 12,54 (5CH_{3}); 21,19-21,35 (CH_{3} ala); 28,07 (C(CH_{3})_{3}); 50,80-50,89 (CH ala); 66,60-67,18 (C5'); 82,41-82,45 (C(Me)_{3}); 84,82 (C4'); 89,67-89,87 (C1'); 111,44-111,60 (C5); 120,22-120,41 (Ar orto); 125,28-125,31 (Ar para); 127,54-127,65 (C2'); 129,88-129,94 (Ar meta); 133,33-133,47 (C3'); 135,84-136,10 (C6); 150,51 (Ar ipso); 150,65-151,20 (C4); 164,19-164,23 (C2); 172,78-172,93 (CO ala).C 13 (CDCl 3): 12.54 (5CH 3); 21.19-21.35 (CH 3 wing); 28.07 (C (CH 3) 3); 50.80-50.89 (CH to); 66.60-67.18 (C5 '); 82.41-82.45 (C (Me) 3); 84.82 (C4 '); 89.67-89.87 (C1 '); 111.44-111.60 (C5); 120.22-120.41 (Ar ortho); 125.28-125.31 (Ar para); 127.54-127.65 (C2 '); 129.88-129.94 (Ar meta); 133.33-133.47 (C3 '); 135.84-136.10 (C6); 150.51 (Ar ipso); 150.65-151.20 (C4); 164.19-164.23 (C2); 172.78-172.93 (CO wing).
Masa (matriz NOBA): C_{23}H_{30}O_{8}N_{3}P: 508 (MH^{+}º, 82); 530 (mº^{+}Na, 48).Mass (NOBA matrix): C 23 H 30 O 8 N 3 P: 508 (MH + 82, 82); 530 (m <+> Na, 48).
Cf 1197Cf 1197
Rendimiento=64%Yield = 64%
P^{31} (CDCl_{3}): 6,44, 6,70 (1:3)P 31 (CDCl 3): 6.44, 6.70 (1: 3)
H^{1} (CDCl_{3}): 1,87º (s, 3H, 5-CH_{3}), 2,42 (t, 2H, CH_{2} ala), 3,22º (m, 2H, CH_{2} ala), 3,62 (s, 3H, 0CH_{3}), 4,09 (m, 1H, H4'), 4,18-4,39 (m, 2H, H5'), 4,97 (s ancho, 1H, NH ala), 5,88º (m, 1H, H2'), 6,32º (m, 1H, H3'), 6,99 (m, 1H, H1'), 7,08-7,38 (m, 5H, Ph y H6), 10,01 (s ancho, 1H, base NH)H 1 (CDCl 3): 1.87 ° (s, 3H, 5-CH 3), 2.42 (t, 2H, CH 2 wing), 3.22 ° (m, 2H, CH2 ala), 3.62 (s, 3H, 0CH3), 4.09 (m, 1H, H4 '), 4.18-4.39 (m, 2H, H5 '), 4.97 (broad s, 1H, NH wing), 5.88 ° (m, 1H, H2 '), 6.32 ° (m, 1H, H3'), 6.99 (m, 1H, H1 '), 7.08-7.38 (m, 5H, Ph and H6), 10.01 (wide s, 1H, base NH)
C^{13} (CDCl_{3}): 14,52 (5-CH_{3}), 37,80º (CH_{2} ala), 39,28º (CH_{2} ala), 53,91º (0CH_{3}), 68,57º (d, J = 3,92 Hz, C5'), 86,90 (d, J = 8,38 Hz, C4'), 91,68º (C1'), 113,40º (C5), 122,34 (d, J = 4,68 Hz, orto-Ph), 127,23 (C2'), 129,55º (para-Ph), 131,81º (meta-Ph), 135,45º (C6), 137,99º (C3'), 152,60º (d, J = 5,96 Hz, ipso-Ph), 153,44 (C2), 166,58 (C4), 174,55º (COO)C 13 (CDCl 3): 14.52 (5-CH 3), 37.80 ° (CH 2 wing), 39.28 ° (CH 2 wing), 53.91 ° (0CH 3), 68.57 ° (d, J = 3.92 Hz, C5 '), 86.90 (d, J = 8.38 Hz, C4 '), 91.68 ° (C1'), 113.40 ° (C5), 122.34 (d, J = 4.68 Hz, ortho-Ph), 127.23 (C2 '), 129.55 ° (para-Ph), 131.81º (meta-Ph), 135.45º (C6), 137.99º (C3 '), 152.60º (d, J = 5.96 Hz, ipso-Ph), 153.44 (C2), 166.58 (C4), 174.55º (COO)
Masa (matriz NOBA): C_{20}H_{24}N_{3}O_{8}P 126 (timina^{+}, 5), 127 (timinaH^{+}, 4), 242 (C_{10}H_{13}PO_{4}N^{+}, 9), 243 (C_{10}H_{14}PO_{4}N^{+}, 3), 465 (M^{+}, 4), 466 (MH^{+}, 8), 467 (MHNa^{+}, 20), 168 (MHNa^{+}, O^{13}, 5), 187 (MNa^{+}, 3), 188 (MHNa^{+}, 97), 189 (MHNa^{+}, C^{13}, 21)Mass (NOBA matrix): C 20 H 24 N 3 O 8 P 126 (thymine +, 5), 127 (thymineH <+>, 4), 242 (C 10 H 13 PO 4 N +, 9), 243 (C 10 H 14 PO 4 N +, 3), 465 (M +, 4), 466 (MH <+>, 8), 467 (MHNa <+>, 20), 168 (MHNa <+>, O <13, 5), 187 (MNa +, 3), 188 (MHNa +, 97), 189 (MHNa +, C 13, twenty-one)
MS de Alta Resolución: encontrado 466,1379 (MH^{+}), C_{20}H_{25}N_{3}O_{8}P requiere 466,1379High Resolution MS: found 466,1379 (MH +), C 20 H 25 N 3 O 8 P requires 466.1379
HPLC: RT = 22,81, 23,27 mins (1:1)HPLC: RT = 22.81, 23.27 mins (1: 1)
Cf 1198Cf 1198
Rendimiento = 65%Yield = 65%
P^{31} (CDCl_{3}): 6,11, 6,66 (1:2)P 31 (CDCl 3): 6.11, 6.66 (1: 2)
H^{1} (CDCl_{3}): 1,78 (m, 2H, CH_{2} GABA), 1,85º (s,3H, 5-CH_{3}), 2,35 (t, 2H, J = 6,95 Hz, CH_{2} GABA), 2,97º (m, 2H, CH_{2} GABA), 3,68 (s, 3H, OCH_{3}), 3,93º (m, 1H, H4'), 4,28º (m, 1H, H5'), 4,35º (m, 1H, H5'), 5,02 (s ancho, 1H, NH GABA), 5,82º (m, 1H, H2'), 6,31 (m, 1H, H3'), 6,98 (m, 1H, H1'), 7,11-7,37 (m, 6H, Ph y H6), 9,91 (s ancho, 1H, base NH)H 1 (CDCl 3): 1.78 (m, 2H, CH 2 GABA), 1.85º (s, 3H, 5-CH3), 2.35 (t, 2H, J = 6.95 Hz, CH 2 GABA), 2.97 ° (m, 2H, CH 2 GABA), 3.68 (s, 3H, OCH 3), 3.93 ° (m, 1H, H4 '), 4.28 ° (m, 1H, H5'), 4.35 ° (m, 1H, H5 '), 5.02 (broad s, 1H, NH GABA), 5.82 ° (m, 1H, H2'), 6.31 (m, 1H, H3 '), 6.98 (m, 1H, H1'), 7.11-7.37 (m, 6H, Ph and H6), 9.91 (wide s, 1H, NH base)
C^{13} (CDCl_{3}): 12,64 (5-CH_{3}), 26,72º (CH_{2} GABA), 32,25º (CH_{2} GABA), 40,98º (CH_{2} GABA), 51,94 (OCH_{3}), 66,93º (C5'), 85,11 (d, J = 8,30 Hz, C4'), 111,40 (C5), 120,46º (d, J = 4,83 Hz, orto-PH), 125,24 (C2'), 127,59º (para-Ph), 129,88º (meta-Ph), 133,68 (C6), 136,28º (C3'), 150,86º (d, J = 6,45 Hz, ipso-Ph), 151,61 (C2), 164,80 (04), 173,86º (COO)C 13 (CDCl 3): 12.64 (5-CH 3), 26.72 ° (CH 2 GABA), 32.25 ° (CH 2 GABA), 40.98 ° (CH 2 GABA), 51.94 (OCH 3), 66.93 ° (C5 '), 85.11 (d, J = 8.30 Hz, C4'), 111.40 (C5), 120.46 ° (d, J = 4.83 Hz, ortho-PH), 125.24 (C2 '), 127.59 ° (para-Ph), 129.88º (meta-Ph), 133.68 (C6), 136.28º (C3 '), 150.86º (d, J = 6.45 Hz, ipso-Ph), 151.61 (C2), 164.80 (04), 173.86º (COO)
Masa (matriz NOBA): C_{21}H_{26}N_{3}O_{8}P: 127 (timinaH^{+}, 28), 479 (M^{+}, 3), 480 (MH^{+}, 59), 481 (MH^{+}, C^{13}, 17), 501 (MNa^{+}, 3), 502 (MHNa^{+}, 59), 503 (MHNa^{+}, C^{13}, 16)Mass (NOBA matrix): C 21 H 26 N 3 O 8 P: 127 (thymine H +, 28), 479 (M +, 3), 480 (MH +, 59), 481 (MH +, C 13, 17), 501 (MNa +, 3), 502 (MHNa +, 59), 503 (MHNa +, C 13, 16)
MS Alta Resolución: encontrado 480,1486 (MH^{+}), C_{21}H_{27}N_{3}O_{8}P requiere 480,1536MS High Resolution: found 480,1486 (MH +), C 21 H 27 N 3 O 8 P requires 480.1536
HPLC: RT 23,90, 24,33 mins (1:1)HPLC: RT 23.90, 24.33 mins (1: 1)
Cf 1200Cf 1200
Rendimiento = 36%Yield = 36%
P^{31} (CDCl_{3}): 2,38, 3,05 (3:1)P 31 (CDCl 3): 2.38, 3.05 (3: 1)
H^{1} (CDCl_{3}): 1,53º (s, 6H, CMe_{2}), 1,91º (s, 3H, 5-CH_{3}), 3,71 (s, 3H, OCH_{3}), 4,31 (m, 2H, H5'), 4,23-4,41 (m, 3H, H4' y H5'), 5,03 (s ancho, 1H, P-NH) 5,89º (m, 1H, H2'), 6,28º (m, 1H, H3'), 6,99-7,31 (m, 7H, Ph, HO y H1'), 9,09 (s ancho, 1H, base NH)H 1 (CDCl 3): 1.53 ° (s, 6H, CMe 2), 1.91 ° (s, 3H, 5-CH 3), 3.71 (s, 3H, OCH 3), 4.31 (m, 2H, H5 '), 4.23-4.41 (m, 3H, H4' and H5 '), 5.03 (broad s, 1H, P-NH) 5.89 ° (m, 1H, H2 '), 6.28 ° (m, 1H, H3 '), 6.99-7.31 (m, 7H, Ph, HO and H1'), 9.09 (s wide, 1H, NH base)
C^{13} (CDCl_{3}): 14,27 (5-CH_{3}), 28,74º (CMe_{2}), 54,81º (OCH_{3}), 58,88 (CMe_{2}), 69,03º (d, C', J = 5,58 Hz), 86,57º (d, J = 7,88 Hz, C4'), 91,51º (C1'), 113,24º (C5), 122,01º (d, J = 4,95 Hz, orto-Ph), 126,88 (C2'), 129,25º (para-Ph), 131,57º (meta-Ph), 135,19º (C6), 137,68º (C3'), 152,52º (d, J = 3,09 Hz, orto-Ph), 153,05 (C2), 166,12 (C4), 177,69º (COO)C 13 (CDCl 3): 14.27 (5-CH 3), 28.74 ° (C Me 2), 54.81 ° (OCH 3), 58.88 ( C Me 2), 69.03 ° (d, C ', J = 5.58 Hz), 86.57 ° (d, J = 7.88 Hz, C4'), 91.51 ° (C1 '), 113 , 24º (C5), 122.01º (d, J = 4.95 Hz, ortho-Ph), 126.88 (C2 '), 129.25º (para-Ph), 131.57º (meta-Ph), 135.19º (C6), 137.68º (C3 '), 152.52º (d, J = 3.09 Hz, ortho-Ph), 153.05 (C2), 166.12 (C4), 177.69º (COO)
MS (matriz NOBA): 354 ((MH-timina)^{+}, pico base), 479 (M^{+}, 3), 480 (MH^{+}, 64), 481 (MH^{+}, C^{13}, 17), 482 (MH^{+}, 2 X C^{13}, 3), 502 (MNa^{+}, 92), 503 (MHNa^{+}, 24)MS (NOBA matrix): 354 ((MH-thymine) +, base peak), 479 (M +, 3), 480 (MH +, 64), 481 (MH +, C 13, 17), 482 (MH +, 2 X C 13, 3), 502 (MNa +, 92), 503 (MHNa +, 24)
MS Alta Resolución: encontrado 480,1503 (MH^{+}), C_{21}H_{27}N_{3}O_{8}P requiere 480,1536MS High Resolution: found 480,1503 (MH +), C 21 H 27 N 3 O 8 P requires 480.1536
HPLC: RT 24,79, 25,29 mins (1:1)HPLC: RT 24.79, 25.29 mins (1: 1)
Cf 1199Cf 1199
Rendimiento = 80%Yield = 80%
P^{31} (CDCl_{3}): 6,90, 6,30 (1:1)P 31 (CDCl 3): 6.90, 6.30 (1: 1)
H^{1} (CDCl_{3}): 1,28 (s, 2H, CH_{2} caproilo), 1,45 (m, 2H, CH_{2} caproilo), 1,58 (m, 2H, CH_{2} caproilo), 1,82º (s, 3H, 5-CH_{3}), 2,28 (m, 2H, CH_{2}, caproilo), 2,87 (m, 2H, CH_{2} caproilo), 3,65 (s, 3H, OCH_{3}), 3,81 (m, 1H, H4'), 4,25 (m, 2H, H5'), 4,95 (s ancho, 1H, NH caproilo), 5,86º (m, 1H, H2'), 6,31º (m, 1H, H3'), 6,98 (m, 1H, H1'), 7,04-7,38º (m, 6H, Ph y H6), 10,12 (s ancho, 1H, base NH)H 1 (CDCl 3): 1.28 (s, 2H, CH 2 caproyl), 1.45 (m, 2H, CH2 caproyl), 1.58 (m, 2H, CH2 caproyl), 1.82 ° (s, 3H, 5-CH 3), 2.28 (m, 2H, CH2, caproyl), 2.87 (m, 2H, CH2caproyl), 3.65 (s, 3H, OCH 3), 3.81 (m, 1H, H4 '), 4.25 (m, 2H, H5'), 4.95 (wide s, 1H, NH caproyl), 5.86 ° (m, 1H, H2 '), 6.31 ° (m, 1H, H3'), 6.98 (m, 1H, H1 '), 7.04-7.38 ° (m, 6H, Ph and H6), 10.12 (wide s, 1H, NH base)
C^{13} (CDCl_{3}): 13,47º (5-CH_{3}), 25,43º (CH_{2} caproilo), 27,04º (CH_{2} caproilo), 32,15º (CH_{2} caproilo), 34,85 (CH_{2} caproilo), 42,30º (CH_{2} caproilo), 52,61 (OCH_{3}), 67,92º (C5'), 85,80 (d, J = 8,22 Hz), 90,68º (C4'), 112,25º (C5), 121,17º (d, J = 4,58 Hz, orto-Ph), 125,99 (C2'), 128,40º (para-Ph), 130,77 (meta-Ph), 134,38º (C6), 137,09º (C3'), 151.69º (d, J = 3,23 Hz, orto-Ph), 152,26 (C2'), 165,36 (C4'), 175,07 (COO)C 13 (CDCl 3): 13.47 ° (5-CH 3), 25.43 ° (CH 2 caproyl), 27.04 ° (CH 2 caproyl), 32.15 ° (CH 2 caproyl), 34.85 (CH 2) caproyl), 42.30 ° (CH 2 caproyl), 52.61 (OCH 3), 67.92 ° (C5 '), 85.80 (d, J = 8.22 Hz), 90.68º (C4'), 112.25º (C5), 121.17º (d, J = 4.58 Hz, ortho-Ph), 125.99 (C2 '), 128.40º (para-Ph), 130.77 (meta-Ph), 134.38º (C6), 137.09º (C3 '), 151.69º (d, J = 3.23 Hz, ortho-Ph), 152.26 (C2 '), 165.36 (C4'), 175.07 (COO)
MS (matriz Cl): 127 (timinaH^{+}, 42), 508 (MH^{+}, 18), 509 (MH^{+}, C^{13}, 5)MS (Cl matrix): 127 (thymineH +, 42), 508 (MH <+>, 18), 509 (MH <+>, C <13>, 5)
MS Alta Resolución: Encontrado 508,1850 (MH^{+}), C_{23}H_{31}N_{3}O_{8}P requiere 508,1849MS High Resolution: Found 508.1850 (MH +), C 23 H 31 N 3 O 8 P requires 508.1849
HPLC: RT 26,33 minsHPLC: RT 26.33 mins
Cf 1216Cf 1216
Rendimiento = 62%Yield = 62%
P^{31} (D_{2}O): 8,84P 31 (D 2 O): 8.84
H^{1} (D_{2}O): 1,73 (3H, s, 5-CH_{3}), 2,18 (2H, m, ala CH_{2}), 2,65 (m, 2H, ala CH_{2}), 3,79 (2m, H, H5'), 4,95 (m, 1H, H4'), 5,76 (m, 1H, H2'), 6,35 (m, 1H, H3'), 6,82 (m, 1H, H1'), 7,47 (s, 1H, H6)H 1 (D 2 O): 1.73 (3H, s, 5-CH 3), 2.18 (2H, m, wing CH 2), 2.65 (m, 2H, wing CH2), 3.79 (2m, H, H5 '), 4.95 (m, 1H, H4'), 5.76 (m, 1H, H2 '), 6.35 (m, 1H, H3'), 6.82 (m, 1H, H1 '), 7.47 (s, 1H, H6)
C^{13} (D_{2}O): 11,81 (5-CH_{3}), 38,51 (ala CH_{2}), 39,45 (d, ala CH_{2}, J = 6,64 Hz), 65,41 (d, C5', J = 4,91 Hz), 86,40 (d, J = 9,20 Hz, C4'), 90,20 (C1'), 111,07 (C5), 125,40 (C2'), 134,66 (C3'), 138,54 (C6), 152,53 (C2), 167,00 (C4), 181,04 (COO)C 13 (D 2 O): 11.81 (5-CH 3), 38.51 (wing CH 2), 39.45 (d, wing CH2, J = 6.64 Hz), 65.41 (d, C5 ', J = 4.91 Hz), 86.40 (d, J = 9.20 Hz, C4 '), 90.20 (C1'), 111.07 (C5), 125.40 (C2 '), 134.66 (C3'), 138.54 (C6), 152.53 (C2), 167.00 (C4), 181.04 (COO)
HPLC: RT = 32,74 mins.HPLC: RT = 32.74 mins.
Cf 1224Cf 1224
Rendimiento = 54%Yield = 54%
P^{31} (D_{2}O): 10,03P 31 (D 2 O): 10.03
H^{1} (D_{2}O): 1,47 (m, 2H, CABA CH_{2}), 1,72 (s, 3H, 5-CH_{3}), 1,98 (m, 2H, GABA CH_{2}), 2,48 (m, 2H, GABA CH_{2}), 3,72 (m, 2H, H5'), 4,91 (m, 1H, H4'), 5,72 (m, 1H, H2'), 6,26 (m, 1H, H3'), 6,72 (m, 1H, H1'), 7,45 (s, 1H, H6').H 1 (D 2 O): 1.47 (m, 2H, CABA CH 2), 1.72 (s, 3H, 5-CH 3), 1.98 (m, 2H, GABA CH2), 2.48 (m, 2H, GABA CH2), 3.72 (m, 2H, H5 '), 4.91 (m, 1H, H4 '), 5.72 (m, 1H, H2'), 6.26 (m, 1H, H3 '), 6.72 (m, 1H, H1'), 7.45 (s, 1H, H6 ').
C^{13} (D_{2}O): 11,79 (5-CH_{3}), 27,99 (d, J = 7,25 Hz, GABA CH_{2}), 34,47 (GABA CH_{2}), 41,17 (GABA CH_{2}), 65,35 (d, J = 4,68 Hz, C5'), 86,38 (d, J = 9,36 Hz, C4'), 90,27 (C1'), 111,47 (C5'), 125,29 (C2'), 134,70 (C3'), 138,68 (C6), 152,47 (C2), 166,95 (C4), 182,32 (COO)C 13 (D 2 O): 11.79 (5-CH 3), 27.99 (d, J = 7.25 Hz, GABA CH 2), 34.47 (GABA CH2), 41.17 (GABA CH2), 65.35 (d, J = 4.68 Hz, C5 '), 86.38 (d, J = 9.36 Hz, C4'), 90.27 (C1 '), 111.47 (C5'), 125.29 (C2 '), 134.70 (C3'), 138.68 (C6), 152.47 (C2), 166.95 (C4), 182.32 (COO)
Cf 1217Cf 1217
Rendimiento = 49%Yield = 49%
P^{31} (D_{2}O): 10,18P 31 (D 2 O): 10.18
H^{1} (D_{2}O): 1,01 (m, 2H, caproilo CH_{2}), 1,21 (m, 2H, caproilo CH_{2}), 1,32 (m, 2H, caproilo CH_{2}), 1,78 (s, 3H, 5-CH_{3}), 2,05 (m, 2H, caproilo CH_{2}), 2,58 (m, 2H, caproilo CH_{2}), 3,78 (m, 2H, H5'), 4,99 (s, 1H, H4'), 6,32 (m, 1H, H3'), 6,82 (m, 1H, H2'), 7,51 (s, 1H, H6)H 1 (D 2 O): 1.01 (m, 2H, caproyl CH2), 1.21 (m, 2H, caproyl CH2), 1.32 (m, 2H, caproyl CH2), 1.78 (s, 3H, 5-CH3), 2.05 (m, 2H, caproyl CH2), 2.58 (m, 2H, caproyl CH2), 3.78 (m, 2H, H5 '), 4.99 (s, 1H, H4'), 6.32 (m, 1H, H3 '), 6.82 (m, 1H, H2'), 7.51 (s, 1H, H6)
C^{13} (D_{2}O): 11,84 (5-CH_{3}), 25,66 (caproilo CH_{2}), 26,46 (caproilo CH_{2}), 31,10 (d, J = 6,82 Hz, caproilo CH_{2}), 37,06 (caproilo CH_{2}), 41,47 (caproilo CH_{2}), 65,37 (d, J = 4,83 Hz, C5'), 86,45 (d, J = 9,74 Hz, C4'), 90,29 (C1'), 111,43 (C5), 125,27 (C2'), 134,80 (C3'), 138,89 (C6), 152,48 (C2), 166,94 (C4), 183,15 (COO).C 13 (D 2 O): 11.84 (5-CH 3), 25.66 (caproyl CH 2), 26.46 (caproyl CH2), 31.10 (d, J = 6.82 Hz, caproyl CH2), 37.06 (caproyl CH2), 41.47 (caproyl CH2), 65.37 (d, J = 4.83 Hz, C5 '), 86.45 (d, J = 9.74 Hz, C4'), 90.29 (C1 '), 111.43 (C5), 125.27 (C2 '), 134.80 (C3'), 138.89 (C6), 152.48 (C2), 166.94 (C4), 183.15 (COO).
\newpage\ newpage
Cf 1098Cf 1098
Rendimiento = 65%Yield = 65%
P^{31} (CDCl_{3}): 6,80, 7,36 ppmP 31 (CDCl 3): 6.80, 7.36 ppm
H^{1} (CDCl_{3}): 1,72 (s, 3H, 5CH_{3}); 2,64, 2,67 (s, 3H, NCH_{3}); 3,62 (s, 3H, OCH_{3}); 3,40-4,10 (m, 2H, CH_{2}); 4,20-4,50 (m, 2H, H5'); 4,97 (s ancho, 1H, H4'), 5,80-5,90 (m, 1H, H2'); 6,30-6,40 (m, 1H, H3'); 6,97 (s ancho, 1H, H1'); 7,00-7,30 (m, 6H, Ar + H6); 9,59 (s ancho, 1H, NH)H 1 (CDCl 3): 1.72 (s, 3H, 5CH 3); 2.64, 2.67 (s, 3H, NCH3); 3.62 (s, 3H, OCH3); 3.40-4.10 (m, 2H, CH2); 4.20-4.50 (m, 2H, H5 '); 4.97 (wide s, 1H, H4 '), 5.80-5.90 (m, 1H, H2 '); 6.30-6.40 (m, 1H, H3 '); 6.97 (broad s, 1H, H1 '); 7.00-7.30 (m, 6H, Ar + H6); 9.59 (wide s, 1H, NH)
C^{13} (CDCl_{3}): 12,35 (5CH_{3});
34,55-34,60-34,65 (NCH_{3});
50,67-50,78-50,87 (CH_{2});
52,10-52,13 (OCH_{3});
62,27-66,77-66,82 C5');
84,71-84,84 (C4'); 89,52-89,82
(C1'); 111,16-111,33 (C5); 120-150
(m, Ar); 127,17-127,40 (C2');
133,25-133,62 (C3'); 135,73-136,11
(C6); 150,85-150,90 (C2);
163,84-163,87 (C4);
170,57-170,60-170,84
(COOCH_{3})C 13 (CDCl 3): 12.35 (5CH 3); 34.55-34.60-34.65 (NCH3); 50.67-50.78-50.87 (CH2); 52.10-52.13 (OCH3); 62.27-66.77-66.82 C5 '); 84.71-84.84 (C4 '); 89.52-89.82 (C1 '); 111.16-111.33 (C5); 120-150 (m, Ar); 127.17-127.40 (C2 '); 133.25-133.62 (C3 '); 135.73-136.11 (C6); 150.85-150.90 (C2); 163.84-163.87 (C4); 170.57-170.60-170.84
( C OOCH_ {3})
Masa: C_{20}H_{24}O_{8}N_{3}P: 488 ((M+Na)+, 100); 466 ((M+H)^{+}, 5)Mass: C 20 H 24 O 8 N 3 P: 488 ((M + Na) +, 100); 466 ((M + H) +, 5)
HPLC: RT = 25,17 y 25,59 minHPLC: RT = 25.17 and 25.59 min
Cf 1133Cf 1133
Rendimiento = 65%Yield = 65%
P^{31} (CDCl_{3}): 0,87, 7,41 ppmP 31 (CDCl 3): 0.87, 7.41 ppm
H^{1} (CDCl_{3}): 1,18-1,24 (m, 2H, CH_{3}CH_{2}); 1,80 (s, 3H, 5CH_{3}); 2,68, 2,71 (s, 3H, NCH_{3}); 3,46-3,65 (m, 2H, NCH_{2}); 3,91-4,45 (m, 2H, H5'); 4,11, 4,13 (s, 3H, CH_{2}CH_{3}); 5,00 (s ancho, 1H, H4'); 5,82-5,88 (m, 1H, H2'); 6,33-6,37 (m, 1H, H3'); 7,00 (s ancho, 1H, H1'); 7,10-7,50 (m, 6H, Ar + H6); 8,75 (s ancho, 1H, NH)H 1 (CDCl 3): 1.18-1.24 (m, 2H, CH 3 C H 2); 1.80 (s, 3H, 5CH3); 2.68, 2.71 (s, 3H, NCH3); 3.46-3.65 (m, 2H, NCH2); 3.91-4.45 (m, 2H, H5 '); 4.11, 4.13 (s, 3H, CH 2 C H 3); 5.00 (broad s, 1H, H4 '); 5.82-5.88 (m, 1H, H2 '); 6.33-6.37 (m, 1H, H3 '); 7.00 (broad s, 1H, H1 '); 7.10-7.50 (m, 6H, Ar + H6); 8.75 (wide s, 1H, NH)
C^{13} (CDCl_{3}):
12,86-12,89 (5CH_{3}); 14,69
(CH_{2}CH_{3}); 35,06-35,11 (NCH_{3});
51,35-51,43-51,51 (NCH_{2}); 61,77
(CH_{2}
CH_{8});
66,77-67,27-67,33 (C5');
85,26-85,36 (C4'); 90,01-90,31
(C1'); 111,69-111,86 (C5); 120-151
(m, Ar); 127,73-127,96 (C2');
133,73-134,10 (C3'); 136,27-136,64
(C6); 151,61 (C2); 164,70 (C4);
170,62-170,66-170,85
(COOCH_{3})C 13 (CDCl 3): 12.86-12.89 (5CH 3); 14.69 (CH 2 C H 3); 35.06-35.11 (NCH3); 51.35-51.43-51.51 (NCH2); 61.77 ( C H2
CH 8); 66.77-67.27-67.33 (C5 '); 85.26-85.36 (C4 '); 90.01-90.31 (C1 '); 111.69-111.86 (C5); 120-151 (m, Ar); 127.73-127.96 (C2 '); 133.73-134.10 (C3 '); 136.27-136.64 (C6); 151.61 (C2); 164.70 (C4); 170.62-170.66-170.85 ( C OOCH 3)
Masa: C_{21}H_{26}O_{8}N_{3}P: 502 ((M+ Na)^{+}, 100); 480 ((M+H)^{+}, 5)Mass: C 21 H 26 O 8 N 3 P: 502 ((M + Na) +, 100); 480 ((M + H) +, 5)
HPLC: RT = 25,84 y 26,65 minHPLC: RT = 25.84 and 26.65 min
Cf 1156Cf 1156
Rendimiento = 52%Yield = 52%
P^{31} (CDCl_{3}): 7,77 ppmP 31 (CDCl 3): 7.77 ppm
H^{1} (CDCl_{3}): 1,75-1,85 (m, 2H, CH_{2}S); 1,90 (s, 3H, SCH_{3}); 2,01, 2,10 (s, 3H, 5CH_{3}); 2,30-2,50 (m, 2H, CH_{2}CH_{2}S); 3,45-3,60 (m, 1H CHNH); 3,94 (s, 2H, H5'); 5,05 (s ancho, 1H, H4'); 5,90-6,00 (m, 1H, H2'); 6,40-6,50 (m, 1H, H3'); 6,93 (s ancho, 1H, H1'); 7,68 (s, 1H, H6)H 1 (CDCl 3): 1.75-1.85 (m, 2H, CH 2 S); 1.90 (s, 3H, SCH 3); 2.01, 2.10 (s, 3H, 5CH3); 2.30-2.50 (m, 2H, CH2CH2S); 3.45-3.60 (m, 1 H C H NH); 3.94 (s, 2H, H5 '); 5.05 (broad s, 1H, H4 '); 5.90-6.00 (m, 1H, H2 '); 6.40-6.50 (m, 1H, H3 '); 6.93 (broad s, 1H, H1 '); 7.68 (s, 1H, H6)
C^{13} (CDCl_{3}): 11,91 (5CH_{3}); 14,46 (SCH_{3}); 29,58 (CH_{3}SCH_{2}CH_{2}); 34,69 (SCH_{2}CH_{2}); 56,42 (CHNH); 65,07-65,13 (C5'); 86,39-86,52 (C4'); 90,14 (Cl'); 111,70 (C5); 125,48 (C2'); 134,77 (C3'); 138,91 (C6); 152,61 (C2); 167,18 (C4); 180,84 (COOH)C 13 (CDCl 3): 11.91 (5CH 3); 14.46 (SCH 3); 29.58 (CH 3 S C H 2 CH 2); 34.69 (SCH 2 CH 2); 56.42 (CHNH); 65.07-65.13 (C5 '); 86.39-86.52 (C4 '); 90.14 (Cl '); 111.70 (C5); 125.48 (C2 '); 134.77 (C3 '); 138.91 (C6); 152.61 (C2); 167.18 (C4); 180.84 (COOH)
Masa: C_{15}H_{22}O_{8}N_{3}PS: 434 ((M-1), 100); 435 ((M), 15)Mass: C 15 H 22 O 8 N 3 PS: 434 ((M-1), 100); 435 ((M), 15)
HPLC: RT = 31,38 minHPLC: RT = 31.38 min
Cf 1163Cf 1163
Rendimiento = 75%Yield = 75%
P^{31} (CDCl_{3}): 11,72 ppmP 31 (CDCl 3): 11.72 ppm
H^{1} (CDCl_{3}): 1,83 (s, 3H, 5CH_{3}); 3,29 (d, CH_{2}, J = 7,9Hz); 3,85-3,92 (m, 2H, H5'); 5,00 (s, 1H, H4'); 5,85-5,88 (m, 1H, H2'); 6,38-6,41 (m, 1H, H3'), 6,88-6,90 (s ancho, 1H H1'); 7,54 (s, 1H, H6)H 1 (CDCl 3): 1.83 (s, 3H, 5CH 3); 3.29 (d, CH2, J = 7.9Hz); 3.85-3.92 (m, 2H, H5 '); 5.00 (s, 1H, H4 '); 5.85-5.88 (m, 1H, H2 '); 6.38-6.41 (m, 1H, H3 '), 6.88-6.90 (s wide, 1H H1 '); 7.54 (s, 1H, H6)
C^{13} (CDCl_{3}): 19,09 (5CH_{3}); 52,24 (CH_{2}); 72,74-72,81 (C5'); 93,61-93,73 (C4'); 97,57 (C1'); 119,08 (C5); 132,80 (C2'); 141,89 (C3'); 145,74 (C6); 159,87 (C2); 174,34 (C4); 186,03-186,15 (COOH)C 13 (CDCl 3): 19.09 (5CH 3); 52.24 (CH2); 72.74-72.81 (C5 '); 93.61-93.73 (C4 '); 97.57 (C1 '); 119.08 (C5); 132.80 (C2 '); 141.89 (C3 '); 145.74 (C6); 159.87 (C2); 174.34 (C4); 186.03-186.15 (COOH)
Masa: C_{12}H_{16}O_{8}N_{3}P: 360 ((M-1), 100); 361 ((M), 15)Mass: C_ {12} H_ {16} O_ {8} N_ {3} P: 360 ((M-1), 100); 361 ((M), 15)
HPLC: RT = 32,57 minHPLC: RT = 32.57 min
Cf 1186Cf 1186
Rendimiento = 82%Yield = 82%
P^{31} (CDCl_{3}): 4,59, 5,16 ppmP 31 (CDCl 3): 4.59, 5.16 ppm
H^{1} (CDCl_{3}): 0,91-0,99 (m, 6H, CH_{3} + CH_{3}); 1,09-1,26 (CHCH_{3}); 1,28-1,56 (m, 2H, CH_{2}); 1,92, 1,97 (s, 3H, 5CH_{3}); 3,60-3,77 (m, 1H, CHNH); 3,77 (s, 3H, OCH_{3}); 3,88-3,99 (m, 1H, NHCH); 4,30-4,52 (m, 2H, H5'); 5,11-5,13 (m, 1H, H4'); 5,95-6,00 (m, 1H, H2'); 6,35-6,45 (m, 1H, H3'); 7,10-7,13 (m, 1H, H1'); 7,16-7,45 (m, 6H, Ar + H6); 8,68 (s ancho, 1H, NH)H 1 (CDCl 3): 0.91-0.99 (m, 6H, CH 3 + CH 3); 1.09-1.26 (C H CH 3); 1.28-1.56 (m, 2H, CH2); 1.92, 1.97 (s, 3H, 5CH3); 3.60-3.77 (m, 1H, C H NH); 3.77 (s, 3H, OCH3); 3.88-3.99 (m, 1H, N H CH); 4.30-4.52 (m, 2H, H5 '); 5.11-5.13 (m, 1H, H4 '); 5.95-6.00 (m, 1H, H2 '); 6.35-6.45 (m, 1H, H3 '); 7.10-7.13 (m, 1H, H1 '); 7.16-7.45 (m, 6H, Ar + H6); 8.68 (broad s, 1H, NH)
C^{13} (CDCl_{3}): 11,90-11,92 (CH_{2}CH_{3}); 12,76-12,81 (5CH_{3}); 15,64 (CHCH_{3}); 25,06-25,14 (CH_{2}CHCH_{3}); 39,39-39,47-39,52-39,60 (CH_{2}); 52,61 (OCH_{3}); 59,38-59,54 (NHCH); 66,94-67,58-67,65 (C5'); 84,91-85,04-85,16 (C4'); 89,94-90,21 (C1'); 111,75-111,87 (C5'); 120-151 (m Ar); 127,82-127,87 (C2'); 133,49-133,69 (C3'); 135,99-136,28 (C6); 151,37 (C2); 164,40 (C4); 173,53-173,59-173,64 (COOCH_{3})C 13 (CDCl 3): 11.90-11.92 (CH 2 CH 3); 12.76-12.81 (5CH3); 15.64 (CH C H 3); 25.06-25.14 (CH 2 C HCH 3); 39.39-39.47-39.52-39.60 (CH2); 52.61 (OCH3); 59.38-59.54 (NHCH); 66.94-67.58-67.65 (C5 '); 84.91-85.04-85.16 (C4 '); 89.94-90.21 (C1 '); 111.75-111.87 (C5 '); 120-151 (m Ar); 127.82-127.87 (C2 '); 133.49-133.69 (C3 '); 135.99-136.28 (C6); 151.37 (C2); 164.40 (C4); 173.53-173.59-173.64 ( C OOCH 3)
Masa: C_{23}H_{30}O_{8}N_{3}P 529,91 ((M + Na)^{+}, 100)Mass: C 23 H 30 O 8 N 3 P 529.91 ((M + Na) +, 100)
HPLC: RT = 30,52 y 31,14 minHPLC: RT = 30.52 and 31.14 min
Cf 1187Cf 1187
Rendimiento = 68%Yield = 68%
P^{31} (CDCl_{3}): 7,58 ppmP 31 (CDCl 3): 7.58 ppm
H^{1} (CDCl_{3}): 1,70 (s, 3H, 5CH_{3}); 2,64-2,80 (m, 2H, CH_{2}Ph); 3,57-3,64 (m, 1H, CHNH); 3,68-3,70 (m, 2H, H5'); 4,85 (s, 1H, H4'); 5,73-5,75 (m, 1H, H2'); 6,26-6,29 (m, 1H, H3'); 6,74-6,75 (m, 1H, H1'); 7,02-7,28 (m, 5H, CH_{2}Ph); 7,44 (s, 1H, H6)H 1 (CDCl 3): 1.70 (s, 3H, 5CH 3); 2.64-2.80 (m, 2H, C H2 Ph); 3.57-3.64 (m, 1H, CHNH); 3.68-3.70 (m, 2H, H5 '); 4.85 (s, 1H, H4 '); 5.73-5.75 (m, 1H, H2 '); 6.26-6.29 (m, 1H, H3 '); 6.74-6.75 (m, 1H, H1 '); 7.02-7.28 (m, 5H, CH2 Ph ); 7.44 (s, 1H, H6)
C^{13} (CDCl_{3}): 11,88 (5CH_{3}); 40,92-40,97 (CH_{2} ala); 58,27 (CH ala); 65,22-65,28 (C5'); 86,36-86,49 (C4'); 90,22 (C1'); 111,63 (C5); 125,38 (C2'); 126-129 (m, Ar); 134,74 (C3'); 138,31-138,48 (C6); 152,40 (C2); 166,81 (C4); 180,87-180,96 (COOH)C 13 (CDCl 3): 11.88 (5CH 3); 40.92-40.97 (CH2 ala); 58.27 (CH wing); 65.22-65.28 (C5 '); 86.36-86.49 (C4 '); 90.22 (C1 '); 111.63 (C5); 125.38 (C2 '); 126-129 (m, Ar); 134.74 (C3 '); 138.31-138.48 (C6); 152.40 (C2); 166.81 (C4); 180.87-180.96 (COOH)
Masa: C_{19}H_{22}O_{8}N_{3}P: 450 ((M-1), 100); 451 ((M, 20)Mass: C 19 H 22 O 8 N 3 P: 450 ((M-1), 100); 451 ((M, 20)
HPLC: RT = 32,11 minHPLC: RT = 32.11 min
Cf 1190Cf 1190
Rendimiento = 67%Yield = 67%
P^{31} (CDCl_{3}): 8,35 ppmP 31 (CDCl 3): 8.35 ppm
H^{1} (CDCl_{3}): 0,72 (t, 6H, (CH_{3})_{2}CH, J = 7,3 Hz); 1,62-1,73 (m, 1H, (CH_{3})_{2}CH); 1,77 (s, 3H, 5CH_{3}); 3,12 (dd, 1H, NHCS, J = 5,6 Hz y 9,4 Hz); 3,80 (dd, 2H, H5', J = 3,5 Hz y 4,4 Hz); 4,92 (s, 1H, H4'); 5,76-5,78 (m, 1H, H2'); 6,31-6,35 (m, 1H, H3'); 6,79-6,81 (m, 1H, H1'); 7,53 (s, 1H, H6)H 1 (CDCl 3): 0.72 (t, 6H, (C H 3) 2 CH, J = 7.3 Hz); 1.62-1.73 (m, 1H, (CH 3) 2 CH); 1.77 (s, 3H, 5CH3); 3.12 (dd, 1H, NHCS, J = 5.6 Hz and 9.4 Hz); 3.80 (dd, 2H, H5 ', J = 3.5 Hz and 4.4 Hz); 4.92 (s, 1H, H4 '); 5.76-5.78 (m, 1H, H2 '); 6.31-6.35 (m, 1H, H3 '); 6.79-6.81 (m, 1H, H1 '); 7.53 (s, 1H, H6)
C^{13} (CDCl_{3}): 11,84 (5CH_{3}); 17,95-18,84 ((CH_{3})_{2}CH); 32,30-32,38 ((CH_{3})_{2}CH); 62,43 (CHNH); 65,18-65,24 (C5'); 86,43-86,58 (C4'); 90,25 (C1'); 111,65 (C5); 125,20 (C2'); 134,90 (C3'); 138,73 (C6); 152,52 (C2); 167,05 (C4); 181,27-181,31 (COOH)C 13 (CDCl 3): 11.84 (5CH 3); 17.95-18.84 (( C H 3) 2 CH); 32.30-32.38 ((CH 3) 2 C H); 62.43 (CHNH); 65.18-65.24 (C5 '); 86.43-86.58 (C4 '); 90.25 (C1 '); 111.65 (C5); 125.20 (C2 '); 134.90 (C3 '); 138.73 (C6); 152.52 (C2); 167.05 (C4); 181.27-181.31 (COOH)
Masa: C_{15}H_{22}O_{8}N_{3}P: 402 ((M-1); 100); 403 ((M)^{-}, 30)Mass: C 15 H 22 O 8 N 3 P: 402 ((M-1); 100); 403 ((M) -, 30)
HPLC: RT = 31,90 minHPLC: RT = 31.90 min
Cf 1192Cf 1192
Rendimiento = 83%Yield = 83%
P^{31} (CDCl_{3}): 7,98 ppmP 31 (CDCl 3): 7.98 ppm
H^{1} (CDCl_{3}): 0,71 (d, 6H, (CH_{3})_{2}CH, J = 6,5 Hz); 1,22-1,34 (m, 2H, CH_{2}); 1,34-1,71 (m, 1H, (CH_{3})_{2}CH); 1,80 (s, 3H, 5CH_{3}); 3,30-3,38 (m, 1H, CHNH); 3,82-3,85 (m, 2H, H5'); 4,95 (s, 1H, H4'); 5,80-5,82 (m, 1H, H2'); 6,35-6,37 (m, 1H, H3'); 6,81-6,82 (m, 1H, H1'); 7,58 (s, 1H, H6)H 1 (CDCl 3): 0.71 (d, 6H, (C H 3) 2 CH, J = 6.5 Hz); 1.22-1.34 (m, 2H, CH2); 1.34-1.71 (m, 1H, (CH 3) 2 C H ); 1.80 (s, 3H, 5CH3); 3.30-3.38 (m, 1H, C H NH); 3.82-3.85 (m, 2H, H5 '); 4.95 (s, 1H, H4 '); 5.80-5.82 (m, 1H, H2 '); 6.35-6.37 (m, 1H, H3 '); 6.81-6.82 (m, 1H, H1 '); 7.58 (s, 1H, H6)
C^{13} (CDCl_{3}): 12,53 (5CH_{3}); 22,88-22,99 ((CH_{3})_{2}CH); 25,28 (CH_{2}); 45,27-45,34 ((CH_{3})_{2}CH); 56,38 (CHNH); 65,74-65,81 (C5'); 87,12-87,25 (C4'); 90,89 (C1'); 112,30 (C5); 125,99 (C2'); 135,49 (C3'); 139,44 (C6); 153,12 (C2); 167,70 (C4); 183,36-182,42 (COOH)C 13 (CDCl 3): 12.53 (5CH 3); 22.88-22.99 (( C H 3) 2 CH); 25.28 (CH2); 45.27-45.34 ((CH 3) 2 C H); 56.38 (CHNH); 65.74-65.81 (C5 '); 87.12-87.25 (C4 '); 90.89 (C1 '); 112.30 (C5); 125.99 (C2 '); 135.49 (C3 '); 139.44 (C6); 153.12 (C2); 167.70 (C4); 183.36-182.42 (COOH)
Masa: C_{16}H_{24}O_{8}N_{3}P: 416 ((M-1), 100); 417 ((M^{-}, 20)Mass: C 16 H 24 O 8 N 3 P: 416 ((M-1), 100); 417 ((M -, 20)
HPLC: RT = 35,02 minHPLC: RT = 35.02 min
Cf 1193Cf 1193
P^{31} (CDCl_{3}): 4,51 ppmP 31 (CDCl 3): 4.51 ppm
H^{1} (CDCl_{3}): 1,25-1,40 (m, 3H, CHCH_{3}); 1,86-1,90 (m, 3H, 5CH_{3}); 3,74-3,90 (m, 4H, OCH_{3} + CH ala); 4,37-4,47 (m, 2H, H5'); 5,08 (s ancho, 1H, H4'); 5,91-5,93 (m, 1H, H2'); 6,38-6,41 (m, 1H, H3'); 7,07-7,09 (m, 1H, H1'); 7,20-7,39 (m, 6H, Ar + H6); 9,04 (s ancho, 1H, NH)H 1 (CDCl 3): 1.25-1.40 (m, 3H, CHC H 3); 1.86-1.90 (m, 3H, 5CH3); 3.74-3.90 (m, 4H, OCH3 + CH wing); 4.37-4.47 (m, 2H, H5 '); 5.08 (broad s, 1H, H4 '); 5.91-5.93 (m, 1H, H2 '); 6.38-6.41 (m, 1H, H3 '); 7.07-7.09 (m, 1H, H1 '); 7.20-7.39 (m, 6H, Ar + H6); 9.04 (broad s, 1H, NH)
C^{13} (CDCl_{3}): 10,85 (5CH_{3}); 19,38-19,45 (CHCH_{3}); 48,71 (CHCH_{3}); 51,14 (OCH_{3}); 64,91-64,97 (C5'); 83,11-83,22 (C4'); 88,03 (C1'); 109,77 (C5); 118-149 (m, Ar); 125,84 (C2'); 131,88 (C3'); 134,44 (C6); 149,34 (C2); 162,35 (C4); 172,53-172,62 (CO ala)C 13 (CDCl 3): 10.85 (5CH 3); 19.38-19.45 (CH C H 3); 48.71 ( C HCH 3); 51.14 (OCH3); 64.91-64.97 (C5 '); 83.11-83.22 (C4 '); 88.03 (C1 '); 109.77 (C5); 118-149 (m, Ar); 125.84 (C2 '); 131.88 (C3 '); 134.44 (C6); 149.34 (C2); 162.35 (C4); 172.53-172.62 (CO wing)
Cf 1194Cf 1194
Rendimiento = 41%Yield = 41%
P^{31} (CDCl_{3}): 5,27 ppmP 31 (CDCl 3): 5.27 ppm
H^{1} (CDCl_{3}): 1,55 (s, 3H, 5CH_{3}); 1,56-2,15 (m, 4H, CHCH_{2}CH_{2}); 3,10-3,30 (m, 2H, NCH_{2}); 3,90-4,00 (m, 1H, NCH); 4,20-4,50 (m, 2H, H5'); 5,11 (s, 1H, H4'); 5,89-5,91 (m, 1H, H2'); 6,41-6,44 (m, 1H, H3'); 6,76-6,78 (m, 1H, H1'); 6,99-7,40 (m, 6H, Ar + H6)H 1 (CDCl 3): 1.55 (s, 3H, 5CH 3); 1.56-2.15 (m, 4H, CHC H2 CH2); 3.10-3.30 (m, 2H, NCH2); 3.90-4.00 (m, 1H, NCH); 4.20-4.50 (m, 2H, H5 '); 5.11 (s, 1H, H4 '); 5.89-5.91 (m, 1H, H2 '); 6.41-6.44 (m, 1H, H3 '); 6.76-6.78 (m, 1H, H1 '); 6.99-7.40 (m, 6H, Ar + H6)
C^{13} (CDCl_{3}): 11,84 (5CH_{3}); 25,44-25,56 (CH_{2}CH_{2}N); 31,94-32,06 (CH_{2}CHN); 47,40-47,46 (NCH_{2}); 63,31 (CHN); 67,14-67,21 (C5'); 85,56-85,68 (C4'); 90,69 (C1'); 111,00 (C5), 120-150 (m, Ar), 125,07 (C2'), 134,13 (C3'), 138,26 (C6), 152,67 (C2), 166,64 (C4), 181,32 (COOH)C 13 (CDCl 3): 11.84 (5CH 3); 25.44-25.56 ( C H 2 CH 2 N); 31.94-32.06 ( C H2 CHN); 47.40-47.46 (NCH2); 63.31 (CHN); 67.14-67.21 (C5 '); 85.56-85.68 (C4 '); 90.69 (C1 '); 111.00 (C5), 120-150 (m, Ar), 125.07 (C2 '), 134.13 (C3'), 138.26 (C6), 152.67 (C2), 166.64 ( C4), 181.32 (COOH)
Masa: C_{21}H_{24}O_{8}N_{3}P: 476 ((M-1), 100); 477 ((M)^{-}, 25)Mass: C 21 H 24 O 8 N 3 P: 476 ((M-1), 100); 477 ((M) -, 25)
HPLC: RT = 34,16 minHPLC: RT = 34.16 min
Rendimiento = 67%Yield = 67%
H^{1} (dmso-d6): 8,14 (1H, s, H8), 8,06 (1H, d, H2), 7,07-7,40 (7H, m, Phe-H & NH2), 6,93 (1H, s, H1'), 6,47 (1H, 2d, H3'), 6,21 (1H, d, H3'), 5,96 (1H, m, NH), 5,11 (1H, m, H4'), 4,10 (2H, m, H5'), 3,5-4,83 (1H, 2m, CH ala), 3,52 (3H, d, MeO), 1,08 (3H, 2d, CH_{3} ala)H 1 (dmso-d6): 8.14 (1H, s, H8), 8.06 (1H, d, H2), 7.07-7.40 (7H, m, Phe-H & NH2), 6.93 (1H, s, H1 '), 6.47 (1H, 2d, H3 '), 6.21 (1H, d, H3'), 5.96 (1H, m, NH), 5.11 (1H, m, H4 '), 4.10 (2H, m, H5 '), 3.5-4.83 (1H, 2m, CH wing), 3.52 (3H, d, MeO), 1.08 (3H, 2d, CH 3 ala)
P^{31} (dmso-d6): 4,92, 4,78.P 31 (dmso-d6): 4.92, 4.78.
C^{13} (dmso-d6): 172,909-172,815 (CO ala), 154,663 (C-2), 152,238 (C-6), 149,524-149,442 (Ar-ipso), 148,782 (C-4), 138,006-137,907 (C-8), 132,286-132,205 (C-2'), 128,621 (Ar-meta), 125,384-125,210 (Ar para), 123,928 (C-3'), 119,067-119,00 (Ar orto), 118,508 (C-5), 87,311-87,060 (C-1'), 84,485-84,368 (C-4'), 66,093-65,324 (C-5'), 51,477-51,429 (OMe), 49,109-48,989 (C-H ala), 19,903-19,585 (CH_{3}, ala).C 13 (dmso-d6): 172,909-172,815 (CO wing), 154,663 (C-2), 152,238 (C-6), 149,524-149,442 (Ar-ipso), 148,782 (C-4), 138,006-137,907 (C-8), 132,286-132,205 (C-2 '), 128,621 (Ar-meta), 125,384-125,210 (Ar para), 123,928 (C-3 '), 119,067-119.00 (Ar ortho), 118,508 (C-5), 87,311-87,060 (C-1 '), 84,485-84,368 (C-4 '), 66,093-65,324 (C-5 '), 51,477-51,429 (OMe), 49,109-48,989 (C-H wing), 19,903-19,585 (CH 3, wing).
Masa. Calculada MH^{+}:475,l49. Encontrada: 475,151Mass. Calculated MH +: 475, l49. Found: 475,151
Rendimiento = 65%Yield = 65%
H^{1} (CDCl_{3}): 8,32 (1H, s ancho, H-8), 7,99 (1H, s ancho, H-2), 7,21 (11H, m, Ar-H & H1'), 6,34 (1H, m, H3'), 6,07 (1H, m, H2'), 5,81 (2H, 2s ancho, NH2), 5,08 (3H, 2s ancho, Bz-CH_{2} & H4'), 4,05 (4H, m, NH, CH, H5'), 1,24 (3H, 2d, metil ala, J = 6,9 Hz).H 1 (CDCl 3): 8.32 (1H, broad s, H-8), 7.99 (1H, wide s, H-2), 7.21 (11H, m, Ar-H & H1 '), 6.34 (1H, m, H3'), 6.07 (1H, m, H2 '), 5.81 (2H, 2s wide, NH2), 5.08 (3H, 2s wide, Bz-CH2 & H4 '), 4.05 (4H, m, NH, CH, H5'), 1.24 (3H, 2d, methyl wing, J = 6.9 Hz).
P^{31} (CDCl_{3}): 4,21, 3,98P 31 (CDCl 3): 4.21, 3.98
C^{13} (CDCl_{3}): 173,700 & 173,601 (O-C=o), 156,005 (C-2), 153,728 (C-6), 150,952 & 150,870 (Ar), 150,322 & 150,280 (C-4), 139,484 & 139,368 (C-8), 135,672 (Ar), 133,733 & 133,654 (C-2'), 130,066 (Ar), 129,041, 128,895, 128,635 & 128,601 (Ar), 126,751 & 126,598 (C-3'), 125,375 (Ar), 120,529, 120,463, 120,399, 120,119 & 120,051 (C-5 & Ar), 88,702 & 88,476 (C-1'), 85,907, 85,476, 85,791 & 85,736 (C-4'), 67,632, 67,475 & 67,403 (C-5' y Bz-CH_{2}), 66,805 & 66,745 (C-5'), 50,677 & 50,542 (Ala C-H), 21,399, 21,335, 21,083 & 21,019 (metil Ala).C 13 (CDCl 3): 173,700 & 173,601 (O-C = o), 156,005 (C-2), 153,728 (C-6), 150,952 & 150,870 (Ar), 150,322 & 150,280 (C-4), 139,484 & 139,368 (C-8), 135,672 (Ar), 133,733 & 133,654 (C-2 '), 130,066 (Ar), 129,041, 128,895, 128,635 & 128,601 (Ar), 126,751 & 126,598 (C-3 '), 125,375 (Ar), 120,529, 120,463, 120,399, 120,119 & 120,051 (C-5 & Ar), 88,702 & 88,476 (C-1 '), 85,907, 85,476, 85,791 & 85,736 (C-4 '), 67,632, 67,475 & 67,403 (C-5 'and Bz-CH2), 66,805 & 66,745 (C-5 '), 50,677 & 50,542 (Wing C-H), 21,399, 21,335, 21,083 & 21,019 (methyl To).
Masa: Calculada MH^{+}: 551,181. Encontrada: 551,179.Mass: Calculated MH <+>: 551,181. Found: 551,179.
Rendimiento = 69%Yield = 69%
rmn H^{1} (D_{2}O): 8,09 (1H, s, H8), 7,88 (1H, s, H2), 6,81 (1H, s, H1'), 6,33 (1H, d, H3'), 6,02 (1H, d, H3'), 5,01 (1H, m, H4'), 4,73 (2H, m, H5'), 3,5-4,83 (1H, 2m, CH ala), 0,89 (3H, 2d, CH_{3} ala)rmn H 1 (D 2 O): 8.09 (1H, s, H8), 7.88 (1H, s, H2), 6.81 (1H, s, H1 '), 6.33 (1H, d, H3'), 6.02 (1H, d, H3 '), 5.01 (1H, m, H4'), 4.73 (2H, m, H5 '), 3.5-4.83 (1H, 2m, CH wing), 0.89 (3H, 2d, CH 3 wing)
P^{31} (D_{2}O): 8,34.P 31 (D 2 O): 8.34.
C^{13} (D_{2}O): 183,055 (CO ala), 155,549 (C-2), 152,745 (C-6), 148,643 (C-3), 140,928 (C-8), 134,730 (C-2'), 124,709 (C-3'), 118,527 (C-5), 88,299 (C-1'), 87,199 & 87,073 (C-4'), 65,215-65,149 (C-5'), 52,564 (Alal C-H), 21,435-21,381 (Ala CH_{3}).C 13 (D 2 O): 183.055 (CO wing), 155.549 (C-2), 152,745 (C-6), 148,643 (C-3), 140,928 (C-8), 134,730 (C-2 '), 124,709 (C-3'), 118,527 (C-5), 88,299 (C-1 '), 87,199 & 87,073 (C-4 '), 65,215-65,149 (C-5 '), 52,564 (Alal C-H), 21,435-21,381 (Ala CH 3).
Rendimiento 33%Yield 33%
P^{31} (CDCl_{3}): 4,14, 4,76P 31 (CDCl 3): 4.14, 4.76
H^{1} (CDCl_{3}): 1,81, 1,85 (5CH_{3}); 1,91-2,18 (m, 2H, Gln); 2,24-2,36 (m, 2H, CH_{2} Gln); 3,64 (s, 3H, NMe); 3,69 (s, 3H, OMe); 3,92-4,21 (m, 2H, H5'); 4,23-4,42 (m, 2H, CH Gln, NH Gln); 5,00 (m, 1H, H4'); 5,91 (m, 1H, H2'); 6,31 (m, 1H, H3'); 7,01 (m, 1H, H1'), 7,03-7,34 (m, 6H, Ph, H6); 9,49 (s, 1H, NH)H 1 (CDCl 3): 1.81, 1.85 (5CH 3); 1.91-2.18 (m, 2H, Gln); 2.24-2.36 (m, 2H, CH2 Gln); 3.64 (s, 3H, NMe); 3.69 (s, 3H, OMe); 3.92-4.21 (m, 2H, H5 '); 4.23-4.42 (m, 2H, CH Gln, NH Gln); 5.00 (m, 1H, H4 '); 5.91 (m, 1H, H2 '); 6.31 (m, 1H, H3 '); 7.01 (m, 1H, H1 '), 7.03-7.34 (m, 6H, Ph, H6); 9.49 (s, 1 H, NH)
C^{13} (CDCl_{3}): 12,32-12,36 (5CH_{3}); 29,01-29,42 (CH_{2} Gln); 29,46 (NMe); 51,81 (CH Gln); 52,65 (OMe); 53,65-53,92 (CH_{2} Gln); 66,63-67,33 (C5'); 84,48-84,71 (C4'); 89,57-89,83 (C1'); 111,29-111,44 (C5); 119,98-120,22 (Ph); 125,21-125,26 (Ph); 127,39-127,50 (C2'); 129,74-129,78 (Ph); 133,00-133,25 (C3'); 135,60-135,90 (C6); 150,98 (C2); 164,00-164,09 (C4); 172,96-173,23 (CO, CON)C 13 (CDCl 3): 12.32-12.36 (5CH3); 29.01-29.42 (CH2 Gln); 29.46 (NMe); 51.81 (CH Gln); 52.65 (OMe); 53.65-53.92 (CH2 Gln); 66.63-67.33 (C5 '); 84.48-84.71 (C4 '); 89.57-89.83 (C1 '); 111.29-111.44 (C5); 119.98-120.22 (Ph); 125.21-125.26 (Ph); 127.39-127.50 (C2 '); 129.74-129.78 (Ph); 133.00-133.25 (C3 '); 135.60-135.90 (C6); 150.98 (C2); 164.00-164.09 (C4); 172.96-173.23 (CO, CON)
Masa (ES): H_{23}H_{29}N_{4}O_{9}P: 536 (M+, 100); 537 (MH^{+}, 32)Mass (ES): H_ {23} H_ {29} N_ {4} P: 536 (M +, 100); 537 (MH +, 32)
Rendimiento 75%75% yield
P^{31} (CDCl_{3}): 1,15, 2,20P 31 (CDCl 3): 1.15, 2.20
H^{1} (CDCl_{3}): 1,81, 1,86 (s, 3H, 5CH_{3}); 2,49-2,92 (m, 2H, CH_{2} Gln); 3,64 (s, 3H, NMe); 3,72 (s, 3H, OMe); 4,04-4,26 (m, 2H, H5'); 4,28-4,43 (m, 2H, CH Asn, NH Asn); 5,05 (m, 1H, H4'); 5,89 (m, 1H, H2'); 6,31 (m, 1H, H3'); 7,01 (m, 1H, H1'); 7,14-7,33 (m, 6H, Ph, H6); 8,46 (s, 1H, NH)H 1 (CDCl 3): 1.81, 1.86 (s, 3H, 5CH3); 2.49-2.92 (m, 2H, CH2 Gln); 3.64 (s, 3H, NMe); 3.72 (s, 3H, OMe); 4.04-4.26 (m, 2H, H5 '); 4.28-4.43 (m, 2H, CH Asn, NH Asn); 5.05 (m, 1H, H4 '); 5.89 (m, 1H, H2 '); 6.31 (m, 1H, H3 '); 7.01 (m, 1H, H1 '); 7.14-7.33 (m, 6H, Ph, H6); 8.46 (s, 1 H, NH)
C^{13} (CDCl_{3}): 12,28 (5CH_{3}); 51,01 (CH Asn); 52,09 (OMe); 52,94 (CH_{2} Asn); 84,75 (C4'); 89,60 (C1'); 111,30 (C5); 125-130 (Ph); 127,32-127,48 (C2'); 133,10-133,41 (C3'); 135,94 (C6)C 13 (CDCl 3): 12.28 (5CH 3); 51.01 (CH Asn); 52.09 (OMe); 52.94 (CH2 Asn); 84.75 (C4 '); 89.60 (C1 '); 111.30 (C5); 125-130 (Ph); 127.32-127.48 (C2 '); 133.10-133.41 (C3 '); 135.94 (C6)
Masa (ES): C_{22}H_{27}N_{4}O_{9}P: 522 (M^{+}, 100); 523 (MH^{+}, 31)Mass (ES): C_22 H_ {27} N4 {9} P: 522 (M +, 100); 523 (MH <+>, 31)
Rendimiento 100%100% yield
P^{31} (CDCl_{3}): 4,15, 4,57P 31 (CDCl 3): 4.15, 4.57
H^{1} (CDCl_{3}): 1,74 (s, 3H, 5CH_{3}); 3,16 (m, 2H, CH_{2} Trp); 3,60 (s, 3H, OMe); 3,75-4,05 (m, 2H, H5'); 4,10-4,33 (m, 2H, CH Trp NH Trp); 4,84 (m, 1H, H4'); 5,79 (m, 1H, H2'); 6,15 (m, 1H, H3'); 6,86 (m, 1H, H1'); 6,91 (m, 1H, H6); 7,00-7,49 (m, 10H, Ar); 8,45 (s, 1H, NH Trp); 9,14 (s, 1H, NH)H 1 (CDCl 3): 1.74 (s, 3H, 5CH 3); 3.16 (m, 2H, CH2 Trp); 3.60 (s, 3H, OMe); 3.75-4.05 (m, 2H, H5 '); 4.10-4.33 (m, 2H, CH Trp NH Trp); 4.84 (m, 1H, H4 '); 5.79 (m, 1H, H2 '); 6.15 (m, 1H, H3 '); 6.86 (m, 1H, H1 '); 6.91 (m, 1H, H6); 7.00-7.49 (m, 10H, Ar); 8.45 (s, 1 H, NH Trp); 9.14 (s, 1H, NH)
C^{13} (CDCl_{3}): 14,75 (5CH_{3}); 32,46 (CH_{2} Trp); 54,91 (CH Trp); 57,53-57,61 (OMe); 69 (C5'); 87,06 (C4'); 92,03-92,25 (C1'); 111,63 (C5); 127,60 (C2'); 135,45-135,83 (C3'); 138,11-138,62 (C6); 152,78-153,41 (C2); 166,28-166,40 (C4); 175,85 (CO)C 13 (CDCl 3): 14.75 (5CH 3); 32.46 (CH 2 Trp); 54.91 (CH Trp); 57.53-57.61 (OMe); 69 (C5 '); 87.06 (C4 '); 92.03-92.25 (C1 '); 111.63 (C5); 127.60 (C2 '); 135.45-135.83 (C3 '); 138.11-138.62 (C6); 152.78-153.41 (C2); 166.28-166.40 (C4); 175.85 (CO)
Masa (ES): C_{28}H_{28}N_{4}O_{9}P: 579 (M^{+}, 100); 580 (M^{+}, 43)Mass (ES): C_ {28} H_ {28} N_ {4} P: 579 (M +, 100); 580 (M +, 43)
Las células fueron infectadas con VIH-1 como se ha descrito antes [Balzarini y col., AIDS (1991), 5, 21-28]. En resumen, se infectaron 5 x 10^{5} células por mililitro con VIH-1 o VIH-2 a 100 DICC_{50} (dosis infectiva de cultivo celular al 50%) por mililitro de suspensión celular. Después se transfirieron 100 \mul de la suspensión celular infectada a pocillos de una placa de microtitulación y se mezclaron con 100 \mul de las diluciones apropiadas de los compuestos de ensayo. Al cabo de 4 días se registró microscópicamente la formación de células gigantes en los cultivos celulares infectados por VIH [CEM], y al cabo de 5 días se determinó el número de células viables mediante tinción con azul de tripán de los cultivos celulares infectados con VIH [MT4]. Se definieron la concentración eficaz del 50% (CE_{50}) y la concentración citotóxica del 50% (CC_{50}) como las concentraciones de compuesto requeridas para reducir en un 50% el número de células gigantes o de células viables en los cultivos celulares infectados por el virus o simuladamente infectados, respectivamente.The cells were infected with HIV-1 as described previously [Balzarini et al ., AIDS (1991), 5 , 21-28]. In summary, 5 x 10 5 cells per milliliter were infected with HIV-1 or HIV-2 at 100 DICC 50 (50% cell culture infective dose) per milliliter of cell suspension. Then 100 µl of the infected cell suspension was transferred to wells of a microtiter plate and mixed with 100 µl of the appropriate dilutions of the test compounds. After 4 days, giant cell formation was recorded microscopically in HIV-infected cell cultures [EMF], and after 5 days the number of viable cells was determined by trypan blue staining of HIV-infected cell cultures [MT4] The 50% effective concentration (EC50) and 50% cytotoxic concentration (CC50) were defined as the compound concentrations required to reduce by 50% the number of giant cells or viable cells in the cell cultures infected by the virus or simulated infected, respectively.
Asimismo se evaluaron las actividades anti-VIH-1 y las toxicidades de los compuestos en dos líneas celulares:The activities were also evaluated. anti-HIV-1 and the toxicities of Compounds in two cell lines:
Células C8166. Las células se hicieron crecer en RPMI 1640 con suero de ternera al 10%. Se mezclaron 4 x 10^{4} células por placa de microtitulación con diluciones a la quinta del compuesto antes de la adición de 10 unidades DICC_{50} de la cepa III-B de VIH-1 y se incubaron durante 5-7 días (Betbeder y col., Antiviral Chem. Chemother. 1, 241-247, 1990). Se examinó la formación de sincitios a los 2 días de la infección. Se recogió el fluido del cultivo a los 5-7 días y se midió la producción de antígeno gp120 mediante ELISA (Mahmood y Hay, J. Immunol. Meth., 151, 9-13, 1992). La CE_{50} es aquella concentración de fármaco [en \muM] requerida para reducir la producción de gp120 en un 50%. Se evaluó la viabilidad celular de las células infectadas y no infectadas mediante el método MTT-Formazano (Pauwels y col., J. Virol. Meth. 20, 309-321, 1988). C8166 cells . The cells were grown in RPMI 1640 with 10% calf serum. 4 x 10 4 cells were mixed per microtiter plate with dilutions to the fifth of the compound before the addition of 10 DICC 50 units of strain III-B of HIV-1 and incubated for 5-7 days (Betbeder et al., Antiviral Chem. Chemother. 1, 241-247, 1990). Syncytium formation was examined 2 days after infection. Culture fluid was collected at 5-7 days and gp120 antigen production was measured by ELISA (Mahmood and Hay, J. Immunol. Meth., 151, 9-13, 1992). The EC50 is that concentration of drug [in µM] required to reduce the production of gp120 by 50%. The cell viability of infected and non-infected cells was evaluated by the MTT-Formazano method (Pauwels et al., J. Virol. Meth. 20, 309-321, 1988).
Células JM Las células JM, que son relativamente resistentes a los efectos antivirales de la AZT y algunos de sus derivados, fueron infectadas con cepas de VIH-1 y se evaluaron los efectos antivirales y tóxicos de los compuestos como para las células C8166. Se utilizaron ambas cepas de VIH-1 GB8 y IIIB, sin diferencias detectables en los puntos finales observados. JM cells JM cells, which are relatively resistant to the antiviral effects of AZT and some of its derivatives, were infected with HIV-1 strains and the antiviral and toxic effects of the compounds were evaluated as for C8166 cells. Both strains of HIV-1 GB8 and IIIB were used, with no detectable differences in the observed endpoints.
Cada análisis se llevó a cabo por duplicado, al menos en dos ocasiones separadas, y los datos expresados son la media de cada análisis separado.Each analysis was carried out in duplicate, at less on two separate occasions, and the data expressed are the average of each separate analysis.
Los compuestos de la presente invención han demostrado ser activos frente a VIH-1 y VIH-2 tanto en células TK^{+} como TK^{-} como se ilustra en la Tabla 2.The compounds of the present invention have shown to be active against HIV-1 and HIV-2 in both TK + and TK - cells as It is illustrated in Table 2.
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Como se esperaba, d4T (comparativo) pierde actividad en las células carentes de quinasa (especialmente CEM TK^{-}), mientras el compuesto 730 de la invención conserva una buena actividad tanto en TK^{+} como en TK^{-} frente a VIH-1 y VIH-2. El compuesto 730 de la invención es >1.000 veces más potente que d4T en las células TK^{-}. Sorprendentemente, el compuesto es 100 veces más potente que d4T en los análisis con CEM TK^{-}.As expected, d4T (comparative) loses activity in kinase-free cells (especially EMF TK -), while compound 730 of the invention retains a good activity in both TK + and TK - versus HIV-1 and HIV-2. Compound 730 of the invention is> 1,000 times more potent than d4T in cells TK <->. Surprisingly, the compound is 100 times more powerful. than d4T in the analyzes with CEM TK -.
La potente actividad de los compuestos de la invención es apoyada adicionalmente por los datos de la Tabla 3, que ilustra el índice de actividad, toxicidad y selectividad de una serie de compuestos de la presente invención.The potent activity of the compounds of the The invention is further supported by the data in Table 3, which illustrates the index of activity, toxicity and selectivity of a series of compounds of the present invention.
La potencia antiviral intensificada y la citotoxicidad reducida de los derivados fosfato conducen a grandes mejoras en el índice de selectividad [definido como CC_{50}/CE_{50}] evidenciando las notables mejoras en la eficacia in vivo en comparación con d4T (comparativo).The enhanced antiviral potency and reduced cytotoxicity of phosphate derivatives lead to large improvements in the selectivity index [defined as CC 50 / EC 50], demonstrating the marked improvements in in vivo efficacy compared to d4T (comparative) .
La evidencia de que los compuestos de la presente invención están actuando por medio de una ruta diferente a la de d4T o AZT es proporcionada por los datos de la Tabla 4.The evidence that the compounds of this invention are acting by means of a different route to that of d4T or AZT is provided by the data in Table 4.
Como se puede observar, mientras la potencia de d4T (comparativo) es muy reducida en las cepas resistentes a los nucleósidos, la potencia de los compuestos de la presente invención se mantiene prolongadamente. Así, está claro que los compuestos de la presente invención no están actuando principalmente por medio del derivado nucleósido 5'-trifosfato convencional.As you can see, while the power of d4T (comparative) is greatly reduced in strains resistant to nucleosides, the potency of the compounds of the present invention It stays long. Thus, it is clear that the compounds of the present invention are not acting primarily by means of conventional 5'-triphosphate nucleoside derivative.
Las células MT4 (a 400.000 células/ml) y las células PBL (a 2.000.000 células/ml) fueron expuestas a diferentes concentraciones de 324[H^{3}] e incubadas a 37ºC durante 24 horas. Después las células fueron lavadas dos veces con PBS frío y al sedimento celular se añadieron 400 \mul de metanol frío al 66%. Después dejar reposar en hielo durante 10 minutos, el extracto celular fue centrifugado y el sobrenadante fue analizado mediante HPLC. Como se muestra en la Tabla 5, los niveles de D4T-MP (monofosfato) intracelular aumentaban proporcionalmente en función de la concentración inicial de 324 en las tres líneas celulares sometidas a ensayo. Sin embargo, el incremento de los niveles de D4T-TP (trifosfato) disminuía a las dosis iniciales de 324 que eran superiores a 25 \muM (para las células CEM y MT4) o superiores a 1,0 \muM (para PBL). Sorprendentemente, un metabolito (denominado X) se acumulaba sustancialmente y predominantemente en los tres tipos celulares. La acumulación era proporcional a la concentración de 324 inicial, y, de nuevo, era más baja en PBL que en células CEM y MT4.MT4 cells (at 400,000 cells / ml) and the PBL cells (at 2,000,000 cells / ml) were exposed to different concentrations of 324 [H 3] and incubated at 37 ° C for 24 hours. Then the cells were washed twice with cold PBS and 400 µl of cold methanol was added to the cell pellet 66% After allowing to rest on ice for 10 minutes, the extract cell was centrifuged and the supernatant was analyzed by HPLC As shown in Table 5, the levels of Intracellular D4T-MP (monophosphate) increased proportionally based on the initial concentration of 324 in the three cell lines tested. However the increased levels of D4T-TP (triphosphate) decreased to the initial doses of 324 that were greater than 25 µM (for CEM and MT4 cells) or greater than 1.0 µM (for PBL). Surprisingly, a metabolite (called X) accumulated substantially and predominantly in all three cell types. The accumulation was proportional to the initial 324 concentration, and, again, it was lower in PBL than in CEM and MT4 cells.
Cuando se incubaba 324 1 mM con elevadas concentraciones de esterasa de hígado de cerdo a 37ºC en tampón Tris-HCl conteniendo MgCl_{2} 5 mM, se observaba una formación dependiente del tiempo de un metabolito. Estos metabolitos eluían simultáneamente con el metabolito predominante (X) que se encontró en los extractos celulares después de la incubación de células intactas con 324[H^{3}]. El metabolito X corresponde a un compuesto de fórmula (10), donde Y es oxígeno, X^{1} es NH, X^{2} es oxígeno, B es timina, R^{1} es Me, R^{2} es hidrógeno.When incubating 324 1 mM with elevated Pork liver esterase concentrations at 37 ° C in buffer Tris-HCl containing 5 mM MgCl2, was observed a time-dependent formation of a metabolite. These metabolites eluted simultaneously with the predominant metabolite (X) that was found in cell extracts after incubation of intact cells with 324 [H3]. He metabolite X corresponds to a compound of formula (10), where Y is oxygen, X 1 is NH, X 2 is oxygen, B is thymine, R 1 is Me, R2 is hydrogen.
Los datos de la gama ampliada de compuestos se presenta en la Tabla 6 (análogos dT4) en los cuales:The data of the extended range of compounds is presented in Table 6 (dT4 analogues) in which:
- Comp. e Inic: hacen referencia a los números de referencia de los compuestos;Comp. and Start: they refer to the reference numbers of the compounds;
- Y: hace referencia al grupo:And does group reference:
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- Z: hace referencia a los grupos T^{1} y T^{2};Z: does reference to the groups T1 and T2;
- B: hace referencia a la base del ácido nucleico heterocíclica, presente en C1' en orientación \beta; se utilizan {}\hskip0,3cm los códigos de las bases de una letra convencionales; los sustituyentes de la pirimidina están en {}\hskip0,4cm C5.B: does reference to the base of the heterocyclic nucleic acid, present in C1 'in β orientation; {} \ hskip0,3cm are used Conventional one-letter base codes; the substituents of the pyrimidine are in {} \ C5.
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Las columnas de datos son, por orden:The columns of data are, in order:
- VIH-1 MT4: CE_{50} en \muM para la inhibición de VIH-1 en células MT4.HIV-1 MT4: EC50 in µM for inhibition of HIV-1 in MT4 cells.
- VIH-2 MT4: CE_{50} en \muM para la inhibición de VIH-2 en células MT4.HIV-2 MT4: EC50 in µM for the inhibition of HIV-2 in MT4 cells.
- CC50 MT4: CC_{50} en \muM para la toxicidad en células MT4.CC50 MT4: CC 50 in µM for toxicity in MT4 cells.
- IH-1 CEM: CE_{50} en \muM para la inhibición de VIH-1 en células CEM.IH-1 CEM: CE 50 in µM for HIV-1 inhibition in CEM cells.
- VIH-2 CEM: CE_{50} en \muM para la inhibición de VIH-2 en células CEM.HIV-2 EMC: EC50 in µM for inhibition of HIV-2 in CEM cells.
- VIH-2 CEM-TK^{-}: CE_{50} en \muM para la inhibición de VIH-2 en células CEM/TK^{-}.HIV-2 CEM-TK -: EC50 in µM for inhibition of HIV-2 in CEM / TK - cells.
- CC50 CEM: CC_{50} en \muM para la toxicidad en células CEM.CC50 CEM: CC 50 in µM for toxicity in CEM cells.
- CE50 MSV: CE_{50} en \muM para la inhibición en MSVCE50 MSV: EC50 in µM for inhibition in MSV
- MCC MSV: Concentración citotóxica mínima en el análisis con MSVMCC MSV: Minimum cytotoxic concentration in the MSV analysis
Cuando los datos de la tabla 6 difieren de los presentados en las Tablas 2 a 5, los primeros datos hacen referencia al resultado medio obtenido de dos o más experimentos repetidos, mientras los últimos hacen referencia a los resultados experimentales individuales.When the data in table 6 differs from those presented in Tables 2 to 5, the first data refer to the average result obtained from two or more repeated experiments, while the latter refer to the results individual experimental
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(Tabla pasa a página siguiente)(Table goes to page next)
Ratones infectados con Virus del Sarcoma de Moloney [MSV] fueron tratados diariamente con placebo, o con d4T [a una de las dos dosis] o con el compuesto 324 a una de las mismas dosis [equimolar].Mice infected with Sarcoma Virus Moloney [MSV] were treated daily with placebo, or with d4T [a one of the two doses] or with compound 324 at one of them [equimolar] dose.
Los ratones NMRI de dos a tres días de edad (pesando 2 gramos) fueron inoculados subcutáneamente (s.c.) en la pata trasera izquierda con 50 \mul de MSV (100 unidades formadoras de focos, medidas mediante determinación in vitro de la transformación inducida por virus de las células fibroblásticas embrionarias C3H murinas). A los 4 o 5 días de la infección, se desarrollaron tumores y rápidamente aumentaron de volumen con el envejecimiento adicional de los ratones. A los 10 - 12 días de la infección, los ratones (que pesaban 5 a 6 gramos) morían de la infección viral. El tratamiento con fármaco comenzaba 1 hora antes de la infección del virus, y adicionalmente se administraba el compuesto diariamente i.p. durante 3 días más. Se calcularon el día medio de inicio del tumor (\pm desviación típica) y la media de días de supervivencia de los ratones (\pm desviación típica) y se evaluó la significación estadística del retraso medio de la formación de tumores y la media de días de supervivencia en los grupos tratados versus el grupo no tratado (de control) mediante un test de la t de Student de dos colas.NMRI mice two to three days old (weighing 2 grams) were inoculated subcutaneously (sc) in the left hind leg with 50 µL of MSV (100 foci-forming units, measured by in vitro determination of virus-induced transformation of murine C3H embryonic fibroblast cells). Within 4 or 5 days of infection, tumors developed and rapidly increased in volume with the additional aging of the mice. At 10-12 days after infection, the mice (weighing 5 to 6 grams) died of the viral infection. Drug treatment began 1 hour before virus infection, and the compound was also administered daily ip for 3 more days. The mean day of onset of the tumor (± standard deviation) and the average days of survival of the mice (± standard deviation) were calculated and the statistical significance of the average delay in tumor formation and the average of days were evaluated survival in the treated groups versus the untreated (control) group using a two-tailed Student's t-test.
Mientras d4T fracasaba al proporcionar cualquier retraso detectable en la aparición de tumores o en la muerte, se observaba un efecto significativo de ambos parámetros con una elevada dosis de compuesto 324, y un efecto sobre el primer parámetro a una dosis baja [Figura 1].While d4T failed to provide any detectable delay in the appearance of tumors or in death, it observed a significant effect of both parameters with a high dose of compound 324, and an effect on the first parameter at a low dose [Figure 1].
Claims (14)
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- Ar es un grupo arilo;Ar is a group aryl;
- Y es oxígeno o azufre;And it is oxygen or sulfur;
- X^{1} se selecciona entre O, NR^{3}, S, CR^{3}R^{4}, CR^{3}W^{1} y CW^{1}W^{2} donde R^{3} y R^{4} se seleccionanX1 se selects between O, NR 3, S, CR 3 R 4, CR 3 W 1 and CW 1 W 2 where R 3 and R 4 are selected
- independientemente entre hidrógeno, grupos alquilo y arilo; y W^{1} y W^{2} son heteroátomos;independently between hydrogen, groups alkyl and aryl; and W1 and W2 are heteroatoms;
- X^{6} es CH_{2} y X^{2} se selecciona (independientemente de X^{1}) entre O, NR^{3}, S, CR^{3}R^{4}, CR^{3}W^{1} y CW^{1}W^{2}X 6 is CH2 and X2 is selected (independently of X1) between O, NR 3, S, CR 3 R 4, CR 3 W 1 and CW 1 W 2
- donde R^{3} y R^{4} se seleccionan independientemente entre hidrógeno, grupos alquilo y arilo; y W^{1} y W^{2} son heteroátomos;where R3 and R 4 are independently selected from hydrogen, groups alkyl and aryl; and W1 and W2 are heteroatoms;
- X^{3} es -CR^{1}R^{2}- donde R^{1} y R^{2} se seleccionan independientemente entre hidrógeno, grupos alquilo y arilo; X^{4} es oxígeno;X3 is -CR 1 R 2 - where R 1 and R 2 are selected independently between hydrogen, alkyl and aryl groups; X 4 it is oxygen;
- X^{5} está ausente;X5 is absent;
- Z se selecciona entre O y NR^{5}, donde R^{5} se selecciona entre hidrógeno, grupos alquilo y arilo;Z is selected between O and NR 5, where R 5 is selected from hydrogen, alkyl and aryl groups;
- J se selecciona entre los grupos alquilo;J is selected between the alkyl groups;
- Q se selecciona entre O, NR^{6}, S, CR^{6}R^{7}, CR^{6}W^{3} y CW^{3}W^{4}, donde R^{6} y R^{7} se seleccionanQ is selected between O, NR 6, S, CR 6 R 7, CR 6 W 3 and CW 3 W 4, where R 6 and R 7 are selected
- independientemente entre hidrógeno, grupos alquilo y arilo; y W^{3} y W^{4} son heteroátomos;independently between hydrogen, groups alkyl and aryl; and W3 and W4 are heteroatoms;
- T^{1} y T^{2} se conectan entre sí y juntos se seleccionan entre los gruposT1 and T2 are connected to each other and together they are selected from among groups
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- B es una base de purina o pirimidinaB is a base of purine or pyrimidine
- Y es oxígeno;And it is oxygen;
- X^{1} es NH;X1 is NH;
- X^{3} es CHR^{1}, donde R^{1} se selecciona entre H, grupos alquilo y arilo; yX3 is CHR1, where R1 is selected from H, alkyl groups and aryl; Y
- Z es oxígeno.Z is oxygen.
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- Y es oxígeno;And it is oxygen;
- X^{1} es NH; yX1 is NH; Y
- X^{3} es CHR^{1}.X3 is CHR1.
- X^{2} es oxígeno; yX2 is oxygen; Y
- Q es oxígeno.What is it oxygen.
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GBGB9505025.8A GB9505025D0 (en) | 1995-03-13 | 1995-03-13 | Chemical compounds |
GB9505025 | 1995-03-13 |
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US (2) | US6455513B1 (en) |
EP (1) | EP0820461B1 (en) |
JP (2) | JPH11506419A (en) |
AT (1) | ATE295849T1 (en) |
AU (1) | AU707196B2 (en) |
CA (1) | CA2215190C (en) |
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ES (1) | ES2242965T3 (en) |
GB (1) | GB9505025D0 (en) |
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US6455513B1 (en) | 2002-09-24 |
EP0820461A1 (en) | 1998-01-28 |
PT820461E (en) | 2005-09-30 |
DE69634747D1 (en) | 2005-06-23 |
US20030120071A1 (en) | 2003-06-26 |
JP2009062359A (en) | 2009-03-26 |
GB9505025D0 (en) | 1995-05-03 |
CA2215190A1 (en) | 1996-09-26 |
AU707196B2 (en) | 1999-07-08 |
AU5009496A (en) | 1996-10-08 |
ATE295849T1 (en) | 2005-06-15 |
MX9706942A (en) | 1998-08-30 |
EP0820461B1 (en) | 2005-05-18 |
US7018989B2 (en) | 2006-03-28 |
DE69634747T2 (en) | 2006-01-12 |
CA2215190C (en) | 2008-12-30 |
JPH11506419A (en) | 1999-06-08 |
NZ303711A (en) | 1999-02-25 |
WO1996029336A1 (en) | 1996-09-26 |
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